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rd Edition
 3rd Edition

’
HARRISON S
TM

HEMATOLOGY AND
ONCOLOGY
 Derived from Harrison’s Principles of Internal Medicine, 19th Edition
Editors
DENNISL. KASPER, md
William Ellery Channing Pro essor o Medicine, Pro essor o
Microbiology and Immunobiology, Department o Microbiology
and Immunobiology, Harvard Medical School; Division o
In ectious Diseases, Brigham and Women’s Hospital
Boston, Massachusetts
STEPHENL. HAUSER, md
Robert A. Fishman Distinguished Pro essor and Chairman,
Department o Neurology, University o Cali ornia, San Francisco
San Francisco, Cali ornia
J. LARRYJAMESON, md, phd
Robert G. Dunlop Pro essor o Medicine;
Dean, Perelman School o Medicine at the University
o Pennsylvania; Executive Vice-President, University o
Pennsylvania or the Health System, Philadelphia, Pennsylvania
ANTHONYS. FAUCI, md
Chie , Laboratory o Immunoregulation; Director, National
Institute o Allergy and In ectious Diseases, National Institutes o
Health Bethesda, Maryland
DANL. LONGO, md
Pro essor o Medicine, Harvard Medical School; Senior Physician,
Brigham and Women’s Hospital; Deputy Editor, New England
Journal o Medicine, Boston, Massachusetts
JOSEPHLOSCALZO, md, phd
Hersey Pro essor o the T eory and Practice o Medicine, Harvard
Medical School; Chairman, Department o Medicine, and
Physician-in-Chie , Brigham and Women’s Hospital, Boston,
Massachusetts
 3rd Edition

’
HARRISON S
TM

HEMATOLOGY AND
ONCOLOGY
EDITOR
Dan L. Longo, MD
Pro essor o Medicine, Harvard Medical School; Senior Physician, Brigham and Women’s
Hospital; Deputy Editor, New England Journal o Medicine,
Boston, Massachusetts

CONTENTS

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 CONTENTS

Contributors viii 12 rans usion Biology and T erapy . . . . . . . . . . . . 146

Je ery S. Dzieczkowski, Kenneth C. Anderson
Pre ace xi

SECTION IV
SECTION I MYELOPROLIFERATIVE DISORDERS
THE CELLULAR BASIS OF HEMATOPOIESIS
13 Polycythemia Vera and Other
1 Hematopoietic Stem Cells . . . . . . . . . . . . . . . . . . . . . 2 Myeloproli erative Neoplasms . . . . . . . . . . . . . . . 158
David . Scadden, Dan L. Longo Jerry L. Spivak

SECTION II SECTION V
CARDINAL MANIFESTATIONS OF HEMATOLOGIC MALIGNANCIES
HEMATOLOGIC DISEASE 14 Acute Myeloid Leukemia . . . . . . . . . . . . . . . . . . . . 168
2 Anemia and Polycythemia. . . . . . . . . . . . . . . . . . . . 10 Guido Marcucci, Clara D. Bloomf eld
John W. Adamson, Dan L. Longo 15 Chronic Myeloid Leukemia . . . . . . . . . . . . . . . . . . 181
3 Bleeding and T rombosis . . . . . . . . . . . . . . . . . . . . 22 Hagop Kantarjian, Jorge Cortes
Barbara A. Konkle 16 Malignancies o Lymphoid Cells . . . . . . . . . . . . . 193
4 Enlargement o Lymph Nodes and Spleen . . . . . . 32 Dan L. Longo
Patrick H. Henry, Dan L. Longo 17 Less Common Hematologic Malignancies . . . . . 216
5 Disorders o Granulocytes and Monocytes . . . . . . 41 Ayalew e eri, Dan L. Longo
Steven M. Holland, John I. Gallin 18 Plasma Cell Disorders . . . . . . . . . . . . . . . . . . . . . . 231
6 Atlas o Hematology and Analysis Nikhil C. Munshi, Dan L. Longo,
o Peripheral Blood Smears . . . . . . . . . . . . . . . . . . . 57 Kenneth C. Anderson
Dan L. Longo 19 Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
David C. Seldin, John L. Berk
SECTION III
ANEMIAS SECTION VI
DISORDERS OF HEMOSTASIS
7 Iron De ciency and Other
Hypoproli erative Anemias . . . . . . . . . . . . . . . . . . . 72 20 Disorders o Platelets and Vessel Wall. . . . . . . . . 254
John W. Adamson Barbara A. Konkle

8 Disorders o Hemoglobin . . . . . . . . . . . . . . . . . . . . 82 21 Coagulation Disorders . . . . . . . . . . . . . . . . . . . . . . 265

Edward J. Benz, Jr. Valder R. Arruda, Katherine A. High

9 Megaloblastic Anemias . . . . . . . . . . . . . . . . . . . . . . 96 22 Arterial and Venous T rombosis . . . . . . . . . . . . . 278

A. Victor Ho rand Jane E. Freedman, Joseph Loscalzo

10 Hemolytic Anemias and Anemia 23 Deep Venous T rombosis and

Due to Acute Blood Loss . . . . . . . . . . . . . . . . . . . . 111 Pulmonary T romboembolism. . . . . . . . . . . . . . . 285
Lucio Luzzatto Samuel Z. Goldhaber

11 Bone Marrow Failure Syndromes Including 24 Antiplatelet, Anticoagulant,

Aplastic Anemia and Myelodysplasia . . . . . . . . . 131 and Fibrinolytic Drugs . . . . . . . . . . . . . . . . . . . . . . 294
Neal S. Young Je rey I. Weitz
v
 vi
vi Contents

SECTION VII 39 Upper Gastrointestinal ract Cancers . . . . . . . . . 542

BIOLOGY OF CANCER Robert J. Mayer
25 Cancer Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 40 Lower Gastrointestinal Cancers . . . . . . . . . . . . . . 551
Pat J. Morin, Je rey M. rent, Robert J. Mayer
Francis S. Collins, Bert Vogelstein
41 umors o the Liver and Biliary ree. . . . . . . . . . 561
26 Cancer Cell Biology . . . . . . . . . . . . . . . . . . . . . . . . 333 Brian I. Carr
Je rey W. Clark, Dan L. Longo
42 Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 576
Elizabeth Smyth, David Cunningham
SECTION VIII
PRINCIPLES OF CANCER PREVENTION 43 Bladder and Renal Cell Carcinomas. . . . . . . . . . . 582
Howard I. Scher, Jonathan E. Rosenberg,
AND TREATMENT
Robert J. Motzer
27 Approach to the Patient with Cancer. . . . . . . . . . 360
44 Benign and Malignant Diseases
Dan L. Longo
o the Prostate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589
28 Prevention and Early Detection o Cancer . . . . . 373 Howard I. Scher, James A. Eastham
Jenni er M. Croswell, Otis W. Brawley,
45 esticular Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 601
Barnett S. Kramer
Robert J. Motzer, Darren R. Feldman,
29 Principles o Cancer reatment . . . . . . . . . . . . . . 386 George J. Bosl
Edward A. Sausville, Dan L. Longo
46 Gynecologic Malignancies . . . . . . . . . . . . . . . . . . . 607
30 In ections in Patients with Cancer . . . . . . . . . . . . 422 Michael V. Seiden
Robert W. Finberg
47 So issue and Bone Sarcomas
31 Hematopoietic Cell ransplantation . . . . . . . . . . 436 and Bone Metastases. . . . . . . . . . . . . . . . . . . . . . . . 616
Frederick R. Appelbaum Shreyaskumar R. Patel, Robert S. Benjamin

32 Neoplasia During Pregnancy . . . . . . . . . . . . . . . . 446 48 Primary and Metastatic umors

Michael F. Greene, Dan L. Longo o the Nervous System . . . . . . . . . . . . . . . . . . . . . . 623
Lisa M. DeAngelis, Patrick Y. Wen
33 Palliative and End-o -Li e Care. . . . . . . . . . . . . . . 454
Ezekiel J. Emanuel 49 Carcinoma o Unknown Primary. . . . . . . . . . . . . 638
Gauri R. Varadhachary, James L. Abbruzzese
SECTION IX
NEOPLASTIC DISORDERS SECTION X
ENDOCRINE NEOPLASIA
34 Cancer o the Skin . . . . . . . . . . . . . . . . . . . . . . . . . . 480
Walter J. Urba, Brendan D. Curti 50 T yroid Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646
J. Larry Jameson, Susan J. Mandel, Anthony P.
35 Head and Neck Cancer . . . . . . . . . . . . . . . . . . . . . 494 Weetman
Everett E. Vokes
51 Endocrine umors o the Gastrointestinal ract
36 Neoplasms o the Lung. . . . . . . . . . . . . . . . . . . . . . 500 and Pancreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 657
Leora Horn , Christine M. Lovly , Robert . Jensen
David H. Johnson
52 Multiple Endocrine Neoplasia . . . . . . . . . . . . . . . 685
37 T ymoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526 Rajesh V. T akker
Dan L. Longo
53 Pheochromocytoma and
38 Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529 Adrenocortical Carcinoma . . . . . . . . . . . . . . . . . . 700
Marc E. Lippman Hartmut P. H. Neumann
 Contents vii

SECTION XI SECTION XII

REMOTE EFFECTS OF CANCER ONCOLOGIC EMERGENCIES AND LATE
EFFECTS AND COMPLICATIONS OF CANCER
54 Paraneoplastic Syndromes:
Endocrinologic/Hematologic . . . . . . . . . . . . . . . . 712
AND ITS TREATMENT
J. Larry Jameson, Dan L. Longo 56 Oncologic Emergencies . . . . . . . . . . . . . . . . . . . . . 732
Rasim Gucalp, Janice P. Dutcher
55 Paraneoplastic Neurologic Syndromes
and Autoimmune Encephalitis . . . . . . . . . . . . . . . 721 57 Late Consequences o Cancer
Josep Dalmau, Myrna R. Rosen eld and Its reatment . . . . . . . . . . . . . . . . . . . . . . . . . . 750
Carl E. Freter, Dan L. Longo
Review and Sel -Assessment . . . . . . . . . . . . . . . . . 757
Charles M. Wiener, Cynthia D. Brown,
Brian Houston
Index 793
 CONTRIBUTORS
Numbers in brackets re er to the chapter(s) written or co-written by the contributor.
James L Abbruzzese, MD
Chie , Division o Medical Oncology, Department o Medicine;
Associate Director, Clinical Research, Duke Cancer Institute,
Durham, North Carolina [49]
John W Adamson, MD
Clinical Pro essor, Division o Hematology/Oncology, Department
o Medicine, University o Cali ornia at San Diego, San Diego,
Cali ornia [2, 7]
Kenneth C Anderson, MD
Kra Family Pro essor o Medicine, Harvard Medical School; Chie ,
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer
Institute, Boston, Massachusetts [12, 18]
Frederick R Appelbaum, MD
Director, Division o Clinical Research, Fred Hutchinson Cancer
Research Center, Seattle, Washington [31]
Valder R Arruda, MD, PhD
Associate Pro essor, Division o Hematology, Department
o Pediatrics, Perelman School o Medicine, University o
Pennsylvania, Philadelphia, Pennsylvania [21]
Robert S Benjamin, MD
P. H. and Faye E. Robinson Distinguished Pro essor o Medicine,
Department o Sarcoma Medical Oncology, T e University o exas
M.D. Anderson Cancer Center, Houston, exas [47]
Edward J Benz, Jr , MD
Richard and Susan Smith Pro essor o Medicine; Pro essor o
Genetics, Harvard Medical School; President and CEO,
Dana-Farber Cancer Institute; Director and Principal Investigator,
Dana-Farber/Harvard Cancer Center; Boston, Massachusetts [8]
John L Berk, MD
Associate Pro essor o Medicine, Boston University School o
Medicine; Clinical Director, Amyloidosis Center, Boston Medical
Center, Boston, Massachusetts [19]
Clara D Bloom eld, MD
Distinguished University Pro essor; William G. Pace, III Pro essor
o Cancer Research; Cancer Scholar and Senior Advisor, T e Ohio
State University Comprehensive Cancer Center; Arthur G. James
Cancer Hospital and Richard J. Solove Research Institute,
Columbus, Ohio [14]
George J Bosl, MD
Pro essor o Medicine, Weill Cornell Medical College; Chair,
Department o Medicine; Patrick M. Byrne Chair in Clinical
Oncology, Memorial Sloan-Kettering Cancer Center, New York,
New York [45]
Otis W Brawley, MD, FACP
Pro essor o Hematology, Medical Oncology, Medicine and
Epidemiology, Emory University; Chie Medical and Scienti c
O cer, American Cancer Society, Atlanta, Georgia [28]
Cynthia D Brown, MD
Associate Pro essor o Clinical Medicine, Division o Pulmonary,
Critical Care, Sleep and Occupational Medicine Indiana University,
Indianapolis, Indiana [Review and Sel -Assessment]
ix
Brian I Carr, MD, PhD, FRCP
IRCCS de Bellis National Center or GI Diseases, Castellana Grotte,
BA, Italy [41]
Je rey W Clark, MD
Associate Pro essor o Medicine, Harvard Medical School; Medical
Director, Clinical rials Core, Dana-Farber Harvard Cancer Center;
Massachusetts General Hospital, Boston, Massachusetts [26]
Francis S Collins, MD, PhD
Director, National Institutes o Health, Bethesda, Maryland [25]
Jorge Cortes, MD
D. B. Lane Cancer Research Distinguished Pro essor or Leukemia
Research; Deputy Chairman; Section Chie o AML and CML,
T e University o exas M.D. Anderson Cancer Center, Houston,
exas [15]
Jenni er M Croswell, MD, MPH
Medical O cer, Center or Oncology Prevention rials Research
Group, Division o Cancer Prevention, National Cancer Institute,
Bethesda, Maryland [28]
David Cunningham, MD, MB, ChB, FRCP
Pro essor, Head o Gastrointestinal/Lymphoma Unit; Director o
Clinical Research, Royal Marsden NHS rust, London, United
Kingdom [42]
Brendan D Curti, MD
Director, Biotherapy Program, Robert W. Franz Cancer
Research Center, Providence Portland Medical Center, Portland,
Oregon [34]
Josep Dalmau, MD, PhD
ICREA Pro essor, Institut d’Investigació Biomèdica August
Pi i Sunyer, University o Barcelona, Barcelona, Spain; Adjunct
Pro essor, University o Pennsylvania, Philadelphia,
Pennsylvania [55]
Lisa M DeAngelis, MD
Pro essor o Neurology, Weill Cornell Medical College; Chair,
Department o Neurology, Memorial Sloan Kettering Cancer
Center, New York, New York [48]
Janice P Dutcher, MD
Associate Director, Cancer Research Foundation o New York,
Chappaqua, New York; Former Pro essor, New York Medical Col-
lege, Valhalla, New York [56]
Je rey S Dzieczkowski, MD
Physician, St. Alphonsus Regional Medical Center; Medical Direc-
tor, Coagulation Clinic, Saint Alphonsus Medical Group, Interna-
tional Medicine and ravel Medicine, Boise, Idaho [12]
James A Eastham, MD
Chie , Urology Service, Florence and T eodore Baumritter/Enid
Ancell Chair o Urologic Oncology, Department o Surgery, Sidney
Kimmel Center or Prostate and Urologic Cancers, Memorial Sloan
Kettering Cancer Center, New York, New York [44]
 x Contributors
Ezekiel J Emanuel, MD, PhD
Chair, Department o Medical Ethics and Health Policy, Levy
University Pro essor, Perelman School o Medicine and Wharton
School, University o Pennsylvania, Philadelphia, Pennsylvania [33]
Darren R Feldman, MD
Associate Pro essor in Medicine, Weill Cornell Medical Center;
Assistant Attending, Genitourinary Oncology Service, Memorial
Sloan-Kettering Cancer Center, New York, New York [45]
Robert W Finberg, MD
Chair, Department o Medicine, University o Massachusetts
Medical School, Worcester, Massachusetts [30]
Jane E Freedman, MD
Pro essor o Medicine, University o Massachusetts Medical School,
Worcester, Massachusetts [22]
Carl E Freter, MD, PhD, FACP
Pro essor o Medicine; Director, Division o Hematology and
Oncology; Associate Director, Cancer Center, Saint Louis
University, St. Louis, Missouri [56]
John I Gallin, MD
Director, Clinical Center, National Institutes o Health, Bethesda,
Maryland [5]
Samuel Z Goldhaber, MD
Pro essor o Medicine, Harvard Medical School; Director,
T rombosis Research Group, Brigham and Women’s Hospital,
Boston, Massachusetts [23]
Michael F Greene, MD
Pro essor o Obstetrics, Gynecology and Reproductive Biology,
Harvard Medical School; Vincent Department o Obstetrics and
Gynecology, Massachusetts General Hospital, Boston,
Massachusetts [32]
Rasim Gucalp, MD
Pro essor o Clinical Medicine, Albert Einstein College o Medicine;
Associate Chairman or Educational Programs, Department o
Oncology; Director, Hematology/Oncology Fellowship, Monte ore
Medical Center, Bronx, New York [56]
Patrick H Henry, MD
Clinical Adjunct Pro essor o Medicine, University o Iowa, Iowa
City, Iowa [4]
Katherine A High, MD
William H. Bennett Pro essor o Pediatrics, Perelman School
o Medicine, University o Pennsylvania; Investigator, Howard
Hughes Medical Institute, T e Children’s Hospital o Philadelphia,
Philadelphia, Pennsylvania [21]
A Victor Hof rand, DM
Emeritus Pro essor o Haematology, University College, London;
Honorary Consultant Haematologist, Royal Free Hospital, London,
United Kingdom [9]
Steven M Holland, MD
Chie , Laboratory o Clinical In ectious Diseases, National Institute
o Allergy and In ectious Diseases, National Institutes o Health,
Bethesda, Maryland [5]
Leora Horn, MD, MSc
Assistant Pro essor, Division o Hematology and Medical
Oncology, Vanderbilt University School o Medicine, Nashville,
ennessee [36]
Brian Houston, MD
Division o Cardiology, Department o Medicine, Johns Hopkins
Hospital, Baltimore, Maryland [Review and Sel -Assessment]
J Larry Jameson, MD, PhD
Robert G. Dunlop Pro essor o Medicine; Dean, Perelman School
o Medicine at the University o Pennsylvania; Executive
Vice President, University o Pennsylvania or the Health System,
Philadelphia, Pennsylvania [50, 54]
Robert Jensen, MD
Chie , Cell Biology Section, National Institutes o Diabetes,
Digestive and Kidney Diseases, National Institutes o Health,
Bethesda, Maryland [51]
David H Johnson, MD
Donald W. Seldin Distinguished Chair in Internal Medicine;
Pro essor and Chairman, Department o Internal Medicine,
University o exas Southwestern School o Medicine, Dallas,
exas [36]
Hagop Kantarjian, MD
Chairman, Leukemia Department; Pro essor o Leukemia,
T e University o exas M.D. Anderson Cancer Center, Houston,
exas [15]
Barbara A Konkle, MD
Pro essor o Medicine, Hematology, University o Washington;
Director, ranslational Research, Puget Sound Blood Center,
Seattle, Washington [3, 20]
Barnett S Kramer, MD, MPH, FACP
Director, Division o Cancer Prevention, National Cancer Institute,
Bethesda, Maryland [28]
Marc E Lippman, MD, MACP, FRCP
Kathleen and Stanley Glaser Pro essor, Department o Medicine,
Deputy Director, Sylvester Comprehensive Cancer Center,
University o Miami Miller School o Medicine, Miami, Florida [38]
Dan L Longo, MD
Pro essor o Medicine, Harvard Medical School; Senior Physician,
Brigham and Women’s Hospital; Deputy Editor, New England
Journal o Medicine, Boston, Massachusetts [1, 2, 4, 6, 16-18, 26, 27,
29, 32, 37, 53, 54, 57]
Joseph Loscalzo, MD, PhD
Hersey Pro essor o the T eory and Practice o Medicine, Harvard
Medical School; Chairman, Department o Medicine; Physician-in-
Chie , Brigham and Women’s Hospital, Boston, Massachusetts [22]
Christine M Lovly, MD, PhD
Academic, Vanderbilt Ingram Cancer Center, Vanderbilt University
School o Medicine, Nashville, ennessee [36]
Lucio Luzzatto, MD, FRCP, FRCPath
Pro essor o Hematology, University o Genova, Genova; Scienti c
Director, Istituto oscano umori, Florence, Italy [10]
Susan J Mandel, MD, MPH
Pro essor o Medicine; Associate Chie , Division o Endocrinology,
Diabetes and Metabolism, Perelman School o Medicine, University
o Pennsylvania, Philadelphia, Pennsylvania [50]
Guido Marcucci, MD
Pro essor o Medicine; John B. and Jane . McCoy Chair in
Cancer Research; Associate Director o ranslational Research,
Comprehensive Cancer Center, T e Ohio State University College
o Medicine, Columbus, Ohio [14]
 Contributors
Robert J Mayer, MD
Faculty Vice President or Academic A airs, Dana-Farber Cancer
Institute; Stephen B. Kay Family Pro essor o Medicine, Harvard
Medical School, Boston, Massachusetts [39, 40]
Pat J Morin, PhD
Senior Director, Scienti c Review and Grants Administration,
American Association or Cancer Research, Philadelphia,
Pennsylvania [25]
Robert J Motzer, MD
Pro essor o Medicine, Joan and San ord Weill College o Medicine
o Cornell University D. Attending Physician, Genitourinary On-
cology Service, Memorial Sloan-Kettering Cancer Center,
New York, New York [43, 45]
Nikhil C Munshi, MD
Pro essor o Medicine, Harvard Medical School; Boston VA
Healthcare System; Director o Basic and Correlative Sciences;
Associate Director, Jerome Lipper Myeloma Center, Dana-Farber
Cancer Institute, Boston, Massachusetts [18]
Hartmut P H Neumann, MD
Universitaet Freiburg, Medizinische Universitaetsklinik,
Freiburg im Breisgau, Germany [53]
Shreyaskumar R Patel, MD
Robert R. Herring Distinguished Pro essor o Medicine; Center
Medical Director, Sarcoma Center, T e University o exas M.D.
Anderson Cancer Center, Houston, exas [47]
Jonathan E Rosenberg, MD
Associate Attending; Section Chie , Non-Prostate Program,
Division o Solid umor Oncology, Department o Medicine,
Memorial Sloan-Kettering Cancer Center, New York,
New York [43]
Myrna R Rosen eld, MD, PhD
Department o Neurology, Hospital Clínic/IDIBAPS, Barcelona,
Spain [55]
Edward A Sausville, MD, PhD
Pro essor o Medicine, University o Maryland School o Medicine;
Associate Director or Clinical Research, Marlene and Stewart
Greenbaum Cancer Center, Baltimore, Maryland [29]
David Scadden, MD
Gerald and Darlene Pro essor o Medicine; Co-Chair, Harvard Stem
Cell Institute; Co-chair, Department o Stem Cell and Regenerative
Biology, Harvard Medical School; Director, Center or Regenerative
Medicine; Chie , Hematologic Malignancies, Cancer Center,
Massachusetts General Hospital, Boston, Massachusetts [1]
Howard I Scher, MD
Pro essor o Medicine, Joan and San ord Weill College o Medicine
o Cornell University; D. Wayne Calloway Chair in Urologic
Oncology; Attending Physician and Chie , Genitourinary Oncology
Service, Department o Medicine, Memorial Sloan-Kettering Cancer
Center, New York, New York [43, 44]
Michael V Seiden, MD, PhD
Chie Medical O cer, McKesson Specialty Health, T e Woodlands,
exas [46]
David C Seldin, MD, PhD
Pro essor, Departments o Medicine and Microbiology; Chie ,
Section o Hematology-Oncology; Director, Amyloidosis Center,
Boston University School o Medicine; Boston Medical Center,
Boston, Massachusetts [19]
xi
Elizabeth Smyth, MB BAO, MSc
Department o Gastrointestinal Oncology, Royal Marsden NHS
Foundation rust, London and Sutton, United Kingdom [42]
Jerry L Spivak, MD
Pro essor o Medicine and Oncology, Hematology Division,
Johns Hopkins University School o Medicine, Baltimore,
Maryland [13]
Ayalew e eri, MD
Pro essor o Medicine and Hematology, Mayo Clinic, Rochester,
Minnesota [17]
Rajesh V T akker, MD, FMedSci, FR
May Pro essor o Medicine, Academic Endocrine Unit, University
o Ox ord; O.C.D.E.M., Churchill Hospital, Headington, Ox ord,
United Kingdom [52]
Je rey M rent, PhD, FACMG
President and Research Director, ranslational Genomics Research
Institute, Phoenix, Arizona; Van Andel Research Institute, Grand
Rapids, Michigan [25]
Walter J Urba, MD, PhD
Director o Research, Earle A. Chiles Research Institute, Providence
Cancer Center, Portland, Oregon [34]
Gauri R Varadhachary, MD
Pro essor, Department o Gastrointestinal Medical Oncology,
T e University o exas M.D. Anderson Cancer Center, Houston,
exas [49]
Bert Vogelstein, MD
Investigator, Howard Hughes Medical Institute; Director, Ludwig
Center at the Sidney Kimmel Comprehensive Cancer Center;
Clayton Pro essor o Oncology and Pathology; Johns Hopkins
Medical Institutions, Baltimore, Maryland [25]
Everett E Vokes, MD
John E. Ultmann Pro essor; Chairman, Department o Medicine;
Physician-in-Chie , University o Chicago Medical Center, Chicago,
Illinois [35]
Anthony P Weetman, MD, DSc
University o She eld, School o Medicine She eld, United
Kingdom [50]
Je rey I Weitz, MD, FRCP(C), FACP
Pro essor o Medicine and Biochemistry, McMaster University;
Executive Director, T rombosis and Atherosclerosis Research
Institute, Hamilton, Ontario, Canada [24]
Patrick Y Wen, MD
Pro essor o Neurology, Harvard Medical School; Director,
Center or Neuro-Oncology, Dana-Farber Cancer Institute;
Director, Division o Neuro-Oncology, Department o Neurology,
Brigham and Women’s Hospital; Dana-Farber Cancer Institute,
Boston, Massachusetts [48]
Charles M Wiener, MD
Vice President o Academic A airs, Johns Hopkins Medicine
International, Pro essor o Medicine and Physiology, Johns Hopkins
School o Medicine, Baltimore, Maryland [Review and Sel -Assessment]
Neal S Young, MD
Chie , Hematology Branch, National Heart, Lung and Blood
Institute; Director, NIH Center or Human Immunology,
Autoimmunity and Inf ammation, National Institutes o Health,
Bethesda, Maryland [11]
 PREFACE
Harrison’s Principles o Internal Medicine has a long
and distinguished tradition in the eld o hematology.
Maxwell Wintrobe, whose work actually established
hematology as a distinct subspecialty o medicine, was
a ounding editor o the book and participated in the
rst seven editions, taking over or insley Harrison
as editor-in-chie on the sixth and seventh editions.
Wintrobe, born in 1901, began his study o blood in
earnest in 1927 as an assistant in medicine at ulane
University in New Orleans. He continued his studies
at Johns Hopkins rom 1930 to 1943 and moved to the
University o Utah in 1943, where he remained until his
death in 1986. He invented a variety o the measures that
are routinely used to characterize red blood cell abnor-
malities, including the hematocrit, the red cell indices,
and erythrocyte sedimentation rate, and de ned the nor-
mal and abnormal values or these parameters, among
many other important contributions in a 50-year career.
Oncology began as a subspecialty much later. It
came to li e as a speci c subdivision within hematol-
ogy. A subset o hematologists with a special interest
in hematologic malignancies began working with che-
motherapeutic agents to treat leukemia and lymphoma
in the mid-1950s and early 1960s. As new agents were
developed and the principles o clinical trial research
were developed, the body o knowledge o oncology
began to become larger and mainly independent rom
hematology. In ormed by the laboratory study o cancer
biology and an expansion in ocus beyond hematologic
neoplasms to tumors o all organ systems, oncology
developed as a separable discipline rom hematology.
T is separation was also ueled by the expansion o the
body o knowledge about clotting and its disorders,
which became a larger part o hematology.
In most academic medical centers, hematology and
oncology remain connected. However, conceptual dis-
tinctions between hematology and oncology have been
made. Di erences are rein orced by separate ellowship
training programs (although many joint training pro-
grams remain), separate board certi cation examina-
tions, separate pro essional organizations, and separate
textbooks describing separate bodies o knowledge. In
some academic medical centers, oncology is not merely
a separate subspecialty division in a Department o
Medicine but is an entirely distinct department in the
medical school with the same standing as the Depart-
ment o Medicine. Economic orces are also at work to
separate hematology and oncology.
Perhaps I am only ref ecting the biases o an old dog,
but I am unenthusiastic about the increasing ractionation
xiii
o medicine subspecialties. T ere are now invasive and
noninvasive cardiologists, gastroenterologists who do
and others who do not use endoscopes, and organ- or
individual disease- ocused subspecialists (diabetolo-
gists, thyroidologists) instead o organ system– ocused
subspecialists (endocrinologists). T is ractionation
has also begun within hematology and oncology. Some
oncologists specialize in a single type o cancer and divi-
sions o hematology have designated experts in clot-
ting. At a time when the body o knowledge that must
be mastered is increasing dramatically, the duration o
training has not been increased to accommodate the
additional learning that is necessary to become highly
skilled. Extraordinary attention has been ocused on
the hours that trainees work. Apparently, the admin-
istrators are more concerned about undocumented
adverse e ects o every third night call on trainees than
they are about the well-documented adverse e ects on
patients o requent hando s o patient responsibility
to multiple caregivers.
Despite the sub-sub-subspecialization that is
pervasive in modern medicine, students, trainees,
general internists, amily medicine physicians, phy-
sicians’ assistants, nurse practitioners, and special-
ists in nonmedicine specialties still require access to
in ormation in hematology and oncology that can
assist them in meeting the needs o their patients.
Given the paucity o single sources o integrated in or-
mation on hematology and oncology, the editors o
Harrison’s Principles o Internal Medicine decided to
pull together the chapters in the “mother book” related
to hematology and oncology and bind them together
in a subspecialty themed book called Harrison’s Hema-
tology and Oncology. T e rst edition o this book
appeared in 2010 and was based on the 17th edition
o Harrison’s Principles o Internal Medicine. A second
edition based on 18th edition o Harrison’s Principles
o Internal Medicine appeared in 2013. T is third edi-
tion is derived rom the 19th edition o Harrison’s
Principles o Internal Medicine. T e book contains 57
chapters organized into 12 sections: (I) T e Cellular
Basis o Hematopoiesis, (II) Cardinal Mani estations
o Hematologic Diseases, (III) Anemias, (IV) Myelo-
proli erative Disorders, (V) Hematologic Malignan-
cies, (VI) Disorders o Hemostasis, (VII) Biology o
Cancer, (VIII) Principles o Cancer Prevention and
reatment, (IX) Neoplastic Disorders, (X) Endocrine
Neoplasia, (XI) Remote E ects o Cancer, and (XII)
Oncologic Emergencies and Late E ects and Compli-
cations o Cancer and Its reatment.
 xiv
T e chapters have been written by physicians who
have made seminal contributions to the body o knowl-
edge in their areas o expertise. T e in ormation is
authoritative and as current as we can make it, given the
time requirements o producing books. Each contains
the relevant in ormation on the genetics, cell biology,
pathophysiology, and treatment o speci c disease enti-
ties. In addition, separate chapters on hematopoiesis,
cancer cell biology, and cancer prevention ref ect the
rapidly growing body o knowledge in these areas that
are the underpinning o our current concepts o diseases
in hematology and oncology. In addition to the actual
in ormation presented in the chapters, a section o test
questions and answers is provided to rein orce impor-
tant principles. A narrative explanation o what is wrong
with the wrong answers should be o urther value in the
preparation o the reader or board examinations.
Preface
T e bringing together o hematology and oncol-
ogy in a single text is unusual and we hope it is use ul.
Like many areas o medicine, the body o knowledge
relevant to the practice o hematology and oncology is
expanding rapidly. New discoveries with clinical impact
are being made at an astounding rate; nearly constant
e ort is required to try to keep pace. It is our hope that
this book is help ul to you in the struggle to master the
daunting volume o new ndings relevant to the care o
your patients.
We are extremely grate ul to Kim Davis and James
Shanahan at McGraw-Hill or their invaluable assistance
in the preparation o this book.
Dan L. Longo, MD
 NOTICE
Medicine is an ever-changing science. As new research and clinical expe-
rience broaden our knowledge, changes in treatment and drug therapy are
required. T e authors and the publisher o this work have checked with
sources believed to be reliable in their e orts to provide in ormation that is
complete and generally in accord with the standards accepted at the time o
publication. However, in view o the possibility o human error or changes in
medical sciences, neither the authors nor the publisher nor any other party
who has been involved in the preparation or publication o this work war-
rants that the in ormation contained herein is in every respect accurate or
complete, and they disclaim all responsibility or any errors or omissions or
or the results obtained rom use o the in ormation contained in this work.
Readers are encouraged to con rm the in ormation contained herein with
other sources. For example and in particular, readers are advised to check the
product in ormation sheet included in the package o each drug they plan to
administer to be certain that the in ormation contained in this work is accu-
rate and that changes have not been made in the recommended dose or in the
contraindications or administration. T is recommendation is o particular
importance in connection with new or in requently used drugs.

Review and sel -assessment questions and answers were taken rom Wiener CM,
Brown CD, Houston B (eds). Harrison’s Sel -Assessment and Board Review, 19th ed.
New York, McGraw-Hill, 2017, ISBN 978-1-259-64288-3.

T e global icons call greater attention to key epidemiologic and clinical di erences in the practice o medicine
throughout the world.

T e genetic icons identi y a clinical issue with an explicit genetic relationship.

xv
 SECTION I

THE CELLULAR BASIS

OF HEMATOPOIESIS
 CH AP TER 1
HEMATOPOIETIC STEM CELLS
David T. Sca d d e n
All o the cell types in the peripheral blood and some
cells in every tissue o the body are derived rom hema-
topoietic (hemo: blood; poiesis: creation) stem cells. I
the hematopoietic stem cell is damaged and can no lon-
ger unction (e.g., due to a nuclear accident), a person
would survive 2–4 weeks in the absence o extraordi-
nary support measures. With the clinical use o hema-
topoietic stem cells, tens o thousands o lives are saved
each year (Chap. 31). Stem cells produce hundreds o
billions o blood cells daily rom a stem cell pool that
is estimated to be only in the tens o thousands. How
stem cells do this, how they persist or many decades
despite the production demands, and how they may
be better used in clinical care are important issues in
medicine.
T e study o blood cell production has become a
paradigm or how other tissues may be organized and
regulated. Basic research in hematopoiesis includes de n-
ing stepwise molecular changes accompanying unc-
tional changes in maturing cells, aggregating cells into
unctional subgroups, and demonstrating hematopoi-
etic stem cell regulation by a specialized microenviron-
ment; these concepts are worked out in hematology,
but they o er models or other tissues. Moreover, these
concepts may not be restricted to normal tissue unc-
tion but extend to malignancy. Stem cells are rare cells
among a heterogeneous population o cell types, and
their behavior is assessed mainly in experimental ani-
mal models involving reconstitution o hematopoiesis.
T us, much o what we know about stem cells is impre-
cise and based on in erences rom genetically manipu-
lated animals.
CARDINAL FUNCTIO NS O F
HEMATO P O IETIC STEM CELLS
All stem cell types have two cardinal unctions: sel -
renewal and di erentiation (Fig. 1-1). Stem cells exist
2
■ Da n L. Lo n g o
to generate, maintain, and repair tissues. T ey unction
success ully i they can replace a wide variety o shorter-
lived mature cells over prolonged periods. T e process
o sel -renewal (see below) assures that a stem cell popu-
lation can be sustained over time. Without sel -renewal,
the stem cell pool would become exhausted and tissue
maintenance would not be possible. T e process o di -
erentiation leads to production o the e ectors o tissue
unction: mature cells. Without proper di erentiation,
the integrity o tissue unction would be compromised
and organ ailure or neoplasia would ensue.
In the blood, mature cells have variable average li e
spans, ranging rom 7 h or mature neutrophils to a ew
months or red blood cells to many years or memory
lymphocytes. However, the stem cell pool is the central,
durable source o all blood and immune cells, maintain-
ing a capacity to produce a broad range o cells rom
a single cell source, yet keeping itsel vigorous over
decades o li e. As an individual stem cell divides, it has
the capacity to accomplish one o three division out-
comes: two stem cells, two cells destined or di erentia-
tion, or one stem cell and one di erentiating cell. T e
ormer two outcomes are the result o symmetric cell
division, whereas the latter indicates a di erent outcome
or the two daughter cells—an event termed asymmetric
cell division. T e relative balance or these types o
outcomes may change during development and under
particular kinds o demands on the stem cell pool.
DEVELOPMENTAL BIOLOGY OF
HEMATOPOIETIC STEM CELLS
During development, blood cells are produced at di -
erent sites. Initially, the yolk sac provides oxygen-
carrying red blood cells, and then the placenta and
several sites o intraembryonic blood cell production
become involved. T ese intraembryonic sites engage
in sequential order, moving rom the genital ridge at a
site where the aorta, gonadal tissue, and mesonephros
 S te m ce ll
S e lf-re newa l Diffe re ntia tion
S te m ce ll
Diffe re ntia te d ce lls
FIGURE 1 -1
Sig n a t u re ch a ra ct e rist ics o t h e ste m ce ll. Stem cells have
two essential eatures: the capacity to di erentiate into a variety
o mature cell types and the capacity or sel -renewal. Intrinsic ac-
tors associated with sel -renewal include expression o Bmi-1, Gf -1,
PTEN, STAT5, Tel/Atv6, p21, p18, MCL-1, Mel-18, RAE28, and HoxB4.
Extrinsic signals or sel -renewal include Notch, Wnt, SHH, and
Tie2/Ang-1. Based mainly on murine studies, hematopoietic stem
cells express the ollowing cell sur ace molecules: CD34, Thy-1
(CD90), c-Kit receptor (CD117), CD133, CD164, and c-Mpl (CD110,
also known as the thrombopoietin receptor).
are emerging to the etal liver and then, in the sec-
ond trimester, to the bone marrow and spleen. As the
location o stem cells changes, the cells they produce
also change. T e yolk sac provides red cells expressing
embryonic hemoglobins while intraembryonic sites
o hematopoiesis generate red cells, platelets, and the
cells o innate immunity. T e production o the cells
o adaptive immunity occurs when the bone marrow is
colonized and the thymus orms. Stem cell proli eration
remains high, even in the bone marrow, until shortly
a er birth, when it appears to dramatically decline. T e
cells in the bone marrow are thought to arrive by the
bloodborne transit o cells rom the etal liver a er cal-
ci cation o the long bones has begun. T e presence o
stem cells in the circulation is not unique to a time win-
dow in development; however, hematopoietic stem cells
appear to circulate throughout li e. T e time that cells
spend reely circulating appears to be brie (measured
in minutes in the mouse), but the cells that do circulate
are unctional and can be used or transplantation. T e
number o stem cells that circulate can be increased in a
number o ways to acilitate harvest and trans er to the
same or a di erent host.
MOBILITY OF HEMATOPOIETIC STEM CELLS
Cells entering and exiting the bone marrow do so
through a series o molecular interactions. Circulating
stem cells (through CD162 and CD44) engage the lec-
tins (carbohydrate binding proteins) P- and E-selectin
on the endothelial sur ace to slow the movement o the 3
cells to a rolling phenotype. Stem cell integrins are then
activated and accomplish rm adhesion between the
stem cell and vessel wall, with a particularly important
C
H
role or stem cell VCAM-1 engaging endothelial VLA-4.
A
P
T
T e chemokine CXCL12 (SDF1) interacting with stem
E
R
cell CXCR4 receptors and ionic calcium interacting
1
with the calcium sensing receptor appear to be impor-
tant in the process o stem cells getting rom the circu-
lation to where they engra in the bone marrow. T is is
H
e
m
particularly true in the developmental move rom etal
a
t
liver to bone marrow.
o
p
o
However, the role or CXCR4 in adults appears to be
i
e
t
i
more related to retention o stem cells in the bone mar-
c
S
t
row rather than the process o getting them there. Inter-
e
m
rupting that retention process through either speci c
C
e
l
molecular blockers o the CXCR4/CXCL12 interaction,
l
s
cleavage o CXCL12, or downregulation o the CXCR4
receptor can all result in the release o stem cells into
the circulation. T is process is an increasingly impor-
tant aspect o recovering stem cells or therapeutic use
as it has permitted the harvesting process to be done
by leukapheresis rather than bone marrow punctures
in the operating room. Granulocyte colony-stimulating
actor and plerixa or, a macrocyclic compound that
can block CXCR4, are both used clinically to mobilize
marrow hematopoietic stem cells or transplant. Re n-
ing our knowledge o how stem cells get into and out
o the bone marrow may improve our ability to obtain
stem cells and make them more e cient at nding their
way to the speci c sites or blood cell production, the
so-called stem cell niche.
HEMATOPOIETIC STEM CELL
MICROENVIRONMENT
T e concept o a specialized microenvironment, or
stem cell niche, was rst proposed to explain why cells
derived rom the bone marrow o one animal could
be used in transplantation and again be ound in the
bone marrow o the recipient. T is niche is more than
just a housing site or stem cells, however. It is an ana-
tomic location where regulatory signals are provided
that allow the stem cells to thrive, to expand i needed,
and to provide varying amounts o descendant daughter
cells. In addition, unregulated growth o stem cells may
be problematic based on their undi erentiated state and
sel -renewal capacity. T us, the niche must also regulate
the number o stem cells produced. In this manner, the
niche has the dual unction o serving as a site o nur-
ture but imposing limits or stem cells: in e ect, acting
as both a nutritive and constraining home.
T e niche or blood stem cells changes with each o
the sites o blood production during development, but
or most o human li e it is located in the bone mar-
row. Within the bone marrow, the perivascular space
4 particularly in regions o trabecular bone serves as a kinase inhibitors, transcription actors like Bmi-1, or
niche. T e mesenchymal and endothelial cells o the microRNA-processing enzymes like Dicer, have little or
marrow microvessels produce kit ligand and CXCL12, di erent e ects on progenitor cells. Hematopoietic stem
both known to be important or hematopoietic stem cells have governing mechanisms that are distinct rom
S
E
cells. Other cell types, such as sympathetic neurons, the cells they generate.
C
T
I
nonmyelinating Schwann cells, macrophages, osteo-
O
N
clasts, and osteoblasts, have been shown to regulate stem
I
cells, but it is unclear whether their e ects are direct or HEMATOPOIETIC STEM CELL
indirect. Extracellular matrix proteins like osteopontin DIFFERENTIATION
also a ect stem cell unction. T e endosteal region is
T
h
Hematopoietic stem cells sit at the base o a branching hier-
e
particularly important or transplanted cells, suggesting
C
e
that there may be distinctive eatures o that region that archy o cells culminating in the many mature cell types
l
l
u
that compose the blood and immune system (Fig. 1-2).
l
a
are yet to be de ned that are important mediators o
r
B
stem cell engra ment. T e unctioning o the niche as T e maturation steps leading to terminally di erenti-
a
s
i
ated and unctional blood cells take place both as a
s
a supportive context or stem cells is o obvious impor-
o
f
tance or maintaining hematopoiesis and in transplan- consequence o intrinsic changes in gene expression
H
e
and niche-directed and cytokine-directed changes in
m
tation. An active area o study involves determining
a
the cells. Our knowledge o the details remains incom-
t
whether the niche is altered in disease and whether
o
p
plete. As stem cells mature to progenitors, precursors,
o
drugs can modi y niche unction to improve trans-
i
e
s
and, nally, mature e ector cells, they undergo a series
i
plantation or normal stem cell unction in hematologic
s
disease. o unctional changes. T ese include the obvious acqui-
sition o unctions de ning mature blood cells, such as
phagocytic capacity or hemoglobin synthesis. T ey also
include the progressive loss o plasticity (i.e., the ability
EXCESS CAPACITY OF HEMATOPOIETIC
to become other cell types). For example, the myeloid
STEM CELLS
progenitor can make all cells in the myeloid series but
In the absence o disease, one never runs out o hema- none in the lymphoid series. As common myeloid pro-
topoietic stem cells. Indeed, serial transplantation stud- genitors mature, they become precursors or either
ies in mice suggest that su cient stem cells are present monocytes and granulocytes or erythrocytes and mega-
to reconstitute several animals in succession, with karyocytes, but not both. Some amount o reversibil-
each animal having normal blood cell production. T e ity o this process may exist early in the di erentiation
act that allogeneic stem cell transplant recipients also cascade, but that is lost beyond a distinct stage in nor-
never run out o blood cells in their li e span, which can mal physiologic conditions. With genetic interventions,
extend or decades, argues that even the limiting num- however, blood cells, like other somatic cells, can be
bers o stem cells provided to them are su cient. How reprogrammed to become a variety o cell types.
stem cells respond to di erent conditions to increase or As cells di erentiate, they may also lose proli era-
decrease their mature cell production remains poorly tive capacity (Fig. 1-3). Mature granulocytes are inca-
understood. Clearly, negative eedback mechanisms pable o proli eration and only increase in number
a ect the level o production o most o the cells, lead- by increased production rom precursors. T e excep-
ing to the normal tightly regulated blood cell counts. tions to the rule are some resident macrophages, which
However, many o the regulatory mechanisms that gov- appear capable o proli eration, and lymphoid cells.
ern production o more mature progenitor cells do not Lymphoid cells retain the capacity to proli erate but
apply or apply di erently to stem cells. Similarly, most have linked their proli eration to the recognition o par-
o the molecules shown to be able to change the size ticular proteins or peptides by speci c antigen recep-
o the stem cell pool have little e ect on more mature tors on their sur ace. Like many tissues with short-lived
blood cells. For example, the growth actor erythropoi- mature cells such as the skin and intestine, blood cell
etin, which stimulates red blood cell production rom proli eration is largely accomplished by a more imma-
more mature precursor cells, has no e ect on stem ture progenitor population. In general, cells within the
cells. Similarly, granulocyte colony-stimulating ac- highly proli erative progenitor cell compartment are
tor drives the rapid proli eration o granulocyte pre- also relatively short-lived, making their way through
cursors but has little or no e ect on the cell cycling o the di erentiation process in a de ned molecular pro-
stem cells. Rather, it changes the location o stem cells gram involving the sequential activation o particular
by indirect means, altering molecules such as CXCL12 sets o genes. For any particular cell type, the di er-
that tether stem cells to their niche. Molecules shown to entiation program is di cult to speed up. T e time it
be important or altering the proli eration, sel -renewal, takes or hematopoietic progenitors to become mature
or survival o stem cells, such as cyclin-dependent cells is ~10–14 days in humans, evident clinically by the
 S te m Ce lls Pro g e nito r Ce lls Line ag e Co mmitte d Mature Ce lls 5
Pre c urs o rs
Aiolos,
LEF1, E2A, PAX-5, AML-1
Co mmo n EBF, PAX-5

C
B Ce ll

H
Lympho id IL4 T Ce ll

A
Pro g e nito r B Ce ll
Pro g e nito r

P
IKAROS,
IL7 Pro g e nito r E2A, NOTCH1,

T
NOTCH,CBF1

E
NOTCH1 GATA3 T Ce ll

R
IL2

1
IL7 IL7
NOTCH1
T/NK Ce ll Id2, Ets -1
IL7 NK Ce ll
Pro g e nito r IL15

H
IKAROS NK Ce ll

e
P U1 Pro g e nito r

m
Plas mac yto id

a
t
FLT-3 Liga nd De ndritic Ce ll

o
IL7

p
He ma topoie tic

o
i
s te m ce ll

e
t
cMyb

i
c
S
Re lB, ICS BP, ld2 Mo no c yto id

t
e
De ndritic Ce ll

m
Multipo te nt FLT-3 Liga nd

C
Pro g e nito r

e
Egn1, Myb

l
l
Mo no c yte

s
Hox, P bx1, M-CS F
Granulo c yte Mo no c yte
S CL, GATA2,
NOTCH Mo no c yte Pro g e nito r
Pro g e nito r Granulo c yte
S CF
C/EBP α
TP O
G-CS F
Bas o phil
GM-CS F IL3, S CF
Granulo c yte Mas t Ce ll
GATA1, FOG Pro g e nito r
Co mmo n C/EBP ε
NF-E2, S CL
Mye lo id Rbtn2
IL5 Eo s ino phil
Pro g e nito r Erythro c yte
IL3, S CF Pro g e nito r
TP O GATA1
RBCs
EP O EP O
Me g akaryo c yte Me g akaryo cyte
Erythro id Pro g e nito r Fli-1
Pro g e nito r TP O AML-1 Plate le ts
TP O

FIGURE 1 -2
Hie ra rch y o h e m a t o p o ie t ic d if e re n t ia t io n . Stem cells are
multipotent cells that are the source o all descendant cells and
have the capacity to provide either long-term (measured in years)
or short-term (measured in months) cell production. Progenitor
cells have a more limited spectrum o cells they can produce and
are generally a short-lived, highly proli erative population also
known as transient ampli ying cells. Precursor cells are cells com-
mitted to a single blood cell lineage but with a continued ability
to proli erate; they do not have all the eatures o a ully mature
cell. Mature cells are the terminally di erentiated product o
the di erentiation process and are the e ector cells o specif c
activities o the blood and immune system. Progress through
the pathways is mediated by alterations in gene expression. The
regulation o the di erentiation by soluble actors and cell-cell
communications within the bone marrow niche are still being
def ned. The transcription actors that characterize particular cell
transitions are illustrated on the arrows; the soluble actors that
contribute to the di erentiation process are in blue. This picture
is a simplif cation o the process. Active research is revealing mul-
tiple discrete cell types in the maturation o B cells and T cells
and has identif ed cells that are biased toward one lineage or
another (rather than uncommitted) in their di erentiation. EPO,
erythropoietin; RBC, red blood cell; SCF, stem cell actor; TPO,
thrombopoietin.

interval between cytotoxic chemotherapy and blood
count recovery in patients.
Although hematopoietic stem cells are generally
thought to have the capacity to orm all cells o the
blood, it is becoming clear that individual stem cells
may not be equal in their di erentiation potential. T at
is, some stem cells are “biased” to become mature cells
o a particular type. In addition, the general concept
o cells having a binary choice o lymphoid or myeloid
di erentiation is not entirely accurate. A cell population
with limited myeloid (monocyte and granulocyte) and
lymphoid potential is now added to the commitment
steps stem cells may undergo.
SELF-RENEWAL
T e hematopoietic stem cell must balance its three poten-
tial ates: apoptosis, sel -renewal, and di erentiation.
6 stem cell cycling and capacity to reconstitute hema-
S te m P roge nitor P re curs or Ma ture topoiesis in adoptive hosts, making them similar to
younger animals. Mature cell numbers are una ected.
T ere ore, molecular events governing the speci c
S
E
Diffe re ntia tion s ta te
unctions o stem cells are being gradually made clear
C
T
I
and o er the potential o new approaches to changing
O
More Le s s
N
stem cell unction or therapy. One critical stem cell
I
S e lf-re ne wa l a bility
unction that remains poorly de ned is the molecular
regulation o sel -renewal.
For medicine, sel -renewal is perhaps the most
T
h
P rolife ra tion a ctivity
e
important unction o stem cells because it is critical
C
e
in regulating the number o stem cells. Stem cell num-
l
l
u
Lymphoid
l
a
e xce ption ber is a key limiting parameter or both autologous and
r
B
(me mory B
allogeneic stem cell transplantation. Were we to have
a
s
a nd T ce lls )
i
s
the ability to use ewer stem cells or expand limited
o
f
numbers o stem cells ex vivo, it might be possible to
H
e
m
FIGURE 1 -3 reduce the morbidity and expense o stem cell harvests
a
t
and enable use o other stem cell sources. Speci cally,
o
Re la t ive u n ct io n o ce lls in t h e h e m a t o p o ie t ic h ie ra rch y.
p
o
umbilical cord blood is a rich source o stem cells. How-
i
The boxes represent distinct unctional eatures o cells in the
e
s
i
ever, the volume o cord blood units is extremely small,
s
myeloid (upper box) versus lymphoid (lower box) lineages.
and there ore, the total number o hematopoietic stem
cells that can be obtained in any single cord blood unit
T e proli eration o cells is generally not associated with is generally only su cient to transplant an individual o
the ability to undergo a sel -renewing division except <40 kg. T is limitation restricts what would otherwise
among memory and B cells and among stem cells. be an extremely promising source o stem cells. wo
Sel -renewal capacity gives way to di erentiation as eatures o cord blood stem cells are particularly impor-
the only option a er cell division when cells leave the tant. (1) T ey are derived rom a diversity o individuals
stem cell compartment, until they have the opportunity that ar exceeds the adult donor pool and there ore can
to become memory lymphocytes. In addition to this overcome the majority o immunologic cross-matching
sel -renewing capacity, stem cells have an additional obstacles. (2) Cord blood stem cells have a large num-
eature characterizing their proli eration machinery. ber o cells associated with them, but (paradoxically)
Stem cells in many mature adult tissues may be hetero- they appear to be associated with a lower incidence o
geneous with some being deeply quiescent, serving as a gra -versus-host disease when compared with simi-
deep reserve, whereas others are more proli erative and larly mismatched stem cells rom other sources. I stem
replenish the short-lived progenitor population. In the cell expansion by sel -renewal could be achieved, the
hematopoietic system, stem cells are generally cytokine- number o cells available might be su cient or use in
resistant, remaining dormant even when cytokines larger adults. An alternative approach to this problem is
drive bone marrow progenitors to proli eration rates to improve the e ciency o engra ment o donor stem
measured in hours. Stem cells, in contrast, are thought cells. Gra engineering is exploring methods o adding
to divide at ar longer intervals, measured in months cell components that may enhance engra ment. Fur-
to years, or the most quiescent cells. T is quiescence thermore, at least some data suggest that depletion o
is di cult to overcome in vitro, limiting the ability to host NK (natural killer) cells may lower the number o
e ectively expand human hematopoietic stem cells. T e stem cells necessary to reconstitute hematopoiesis.
process may be controlled by particularly high levels o Some limited understanding o sel -renewal exists
cyclin-dependent kinase inhibitors like p57 or CDKN1c and, intriguingly, implicates gene products that are
that restrict entry o stem cells into the cell cycle, block- associated with the chromatin state, a high-order orga-
ing the G1-S transition. Exogenous signals rom the nization o chromosomal DNA that inf uences tran-
niche also appear to en orce quiescence, including the scription. T ese include members o the polycomb
activation o the tyrosine kinase receptor ie2 on stem amily, a group o zinc nger–containing transcriptional
cells by angiopoietin 1 on niche cells. regulators that interact with the chromatin structure,
T e regulation o stem cell proli eration also appears contributing to the accessibility o groups o genes or
to change with age. In mice, the cyclin-dependent transcription. One member, Bmi-1, is important in
kinase inhibitor p16INK4a accumulates in stem cells in enabling hematopoietic stem cell sel -renewal through
older animals and is associated with a change in ve di - modi cation o cell cycle regulators such as the cyclin-
erent stem cell unctions, including cell cycling. Lower- dependent kinase inhibitors. In the absence o Bmi-1
ing expression o p16INK4a in older animals improves or o the transcriptional regulator, G -1, hematopoietic
stem cells decline in number and unction. In contrast,
dysregulation o Bmi-1 has been associated with leu-
kemia; it may promote leukemic stem cell sel -renewal
when it is overexpressed. Other transcription regulators
have also been associated with sel -renewal, particularly
homeobox, or “hox,” genes. T ese transcription actors
are named or their ability to govern large numbers o
genes, including those determining body patterning in
invertebrates. HoxB4 is capable o inducing extensive
sel -renewal o stem cells through its DNA-binding
moti . Other members o the hox amily o genes have
been noted to a ect normal stem cells, but they are
also associated with leukemia. External signals that
may inf uence the relative sel -renewal versus di eren-
tiation outcomes o stem cell cycling include speci c
Wnt ligands. Intracellular signal transducing interme-
diates are also implicated in regulating sel -renewal.
T ey include P EN, an inhibitor o the AK pathway,
and S A 5, both o which are downstream o activated
growth actor receptors and necessary or normal stem
cell unctions including sel -renewal, at least in mouse
models. T e connections between these molecules
remain to be de ned, and their role in physiologic regu-
lation o stem cell sel -renewal is still poorly understood.
CANCER IS SIMILAR TO AN O RGAN
WITH SELF-RENEWING CAPACITY
T e relationship o stem cells to cancer is an important
evolving dimension o adult stem cell biology. Cancer
may share principles o organization with normal tis-
sues. Cancer cells are heterogeneous even within a given
patient and may have a hierarchical organization o
cells with a base o stem-like cells capable o the signa-
ture stem cell eatures: sel -renewal and di erentiation.
T ese stem-like cells might be the basis or perpetuation
o the tumor and represent a slowly dividing, rare popu-
lation with distinct regulatory mechanisms, including
a relationship with a specialized microenvironment. A
subpopulation o sel -renewing cells has been de ned
or some, but not all, cancers. A more sophisticated
understanding o the stem cell organization o cancers
may lead to improved strategies or developing new
therapies or the many common and di cult-to-treat
types o malignancies that have been relatively re rac-
tory to interventions aimed at dividing cells.
Does the concept o cancer stem cells provide insight
into the cellular origin o cancer? T e act that some
cells within a cancer have stem cell–like properties
does not necessarily mean that the cancer arose in the
stem cell itsel . Rather, more mature cells could have 7
acquired the sel -renewal characteristics o stem cells.
Any single genetic event is unlikely to be su cient to
enable ull trans ormation o a normal cell to a rankly
C
H
malignant one. Rather, cancer is a multistep process,
A
P
T
and or the multiple steps to accumulate, the cell o
E
R
origin must be able to persist or prolonged periods. It
1
must also be able to generate large numbers o daughter
cells. T e normal stem cell has these properties and,
by virtue o its having intrinsic sel -renewal capability,
H
e
m
may be more readily converted to a malignant pheno-
a
t
type. T is hypothesis has been tested experimentally in
o
p
o
the hematopoietic system. aking advantage o the cell-
i
e
t
i
sur ace markers that distinguish hematopoietic cells o
c
S
t
varying maturity, stem cells, progenitors, precursors,
e
m
and mature cells can be isolated. Power ul trans orming
C
e
l
gene constructs were placed in these cells, and it was
l
s
ound that the cell with the greatest potential to pro-
duce a malignancy was dependent on the trans orming
gene. In some cases, it was the stem cell, but in others,
the progenitor cell unctioned to initiate and perpetuate
the cancer. T is shows that cells can acquire stem cell–
like properties in malignancy.
WHAT ELSE CAN HEMATO P O IETIC
STEM CELLS DO?
Some experimental data have suggested that hemato-
poietic stem cells or other cells mobilized into the circu-
lation by the same actors that mobilize hematopoietic
stem cells are capable o playing a role in healing the
vascular and tissue damage associated with stroke and
myocardial in arction. T ese data are controversial,
and the applicability o a stem cell approach to nonhe-
matopoietic conditions remains experimental. How-
ever, reprogramming technology o ers the potential or
using the readily obtained hematopoietic stem cell as a
source or cells with other capabilities.
T e stem cell, there ore, represents a true dual-edged
sword. It has tremendous healing capacity and is essen-
tial or li e. Uncontrolled, it can threaten the li e it main-
tains. Understanding how stem cells unction, the signals
that modi y their behavior, and the tissue niches that
modulate stem cell responses to injury and disease are
critical or more e ectively developing stem cell–based
medicine. T at aspect o medicine will include the use
o the stem cells and the use o drugs to target stem cells
to enhance repair o damaged tissues. It will also include
the care ul balance o interventions to control stem cells
where they may be dys unctional or malignant.
This page intentionally left blank
 SECTION II

CARDINAL
MANIFESTATIONS OF
HEMATOLOGIC DISEASE
 CH AP TER 2
ANEMIA AND POLYCYTHEMIA
Jo h n W. Ad am so n
HEMATO P O IESIS AND THE
P HYSIO LO GIC BASIS O F
RED CELL P RO DUCTIO N
Hematopoiesis is the process by which the ormed
elements o blood are produced. T e process is regu-
lated through a series o steps beginning with the hema-
topoietic stem cell. Stem cells are capable o producing
red cells, all classes o granulocytes, monocytes, plate-
lets, and the cells o the immune system. T e precise
molecular mechanism—either intrinsic to the stem
cell itsel or through the action o extrinsic actors—
by which the stem cell becomes committed to a given
lineage is not ully de ned. However, experiments in
mice suggest that erythroid cells come rom a common
erythroid/megakaryocyte progenitor that does not
develop in the absence o expression o the GA A-1
and FOG-1 ( riend o GA A-1) transcription actors
(Chap. 1). Following lineage commitment, hematopoi-
etic progenitor and precursor cells come increasingly
under the regulatory in uence o growth actors and
hormones. For red cell production, erythropoietin
(EPO) is the primary regulatory hormone. EPO is
required or the maintenance o committed erythroid
progenitor cells that, in the absence o the hormone,
undergo programmed cell death (apoptosis). T e reg-
ulated process o red cell production is erythropoiesis,
and its key elements are illustrated in Fig. 2-1.
In the bone marrow, the rst morphologically rec-
ognizable erythroid precursor is the pronormoblast.
T is cell can undergo our to ve cell divisions, which
result in the production o 16–32 mature red cells. With
increased EPO production, or the administration o
EPO as a drug, early progenitor cell numbers are ampli-
ed and, in turn, give rise to increased numbers o
erythrocytes. T e regulation o EPO production itsel is
linked to tissue oxygenation.
In mammals, O2 is transported to tissues bound to
the hemoglobin contained within circulating red cells.
10
■ Da n L. Lo n g o
T e mature red cell is 8 µm in diameter, anucleate, dis-
coid in shape, and extremely pliable in order to tra-
verse the microcirculation success ully; its membrane
integrity is maintained by the intracellular generation
o A P. Normal red cell production results in the daily
replacement o 0.8–1% o all circulating red cells in
the body, since the average red cell lives 100–120 days.
T e organ responsible or red cell production is called
the erythron. T e erythron is a dynamic organ made
up o a rapidly proli erating pool o marrow erythroid
precursor cells and a large mass o mature circulating
red blood cells. T e size o the red cell mass re ects
the balance o red cell production and destruction. T e
physiologic basis o red cell production and destruction
provides an understanding o the mechanisms that can
lead to anemia.
T e physiologic regulator o red cell production, the
glycoprotein hormone EPO, is produced and released
by peritubular capillary lining cells within the kidney.
T ese cells are highly specialized epithelial-like cells. A
small amount o EPO is produced by hepatocytes. T e
undamental stimulus or EPO production is the avail-
ability o O2 or tissue metabolic needs. Key to EPO
gene regulation is hypoxia-inducible actor (HIF)-1α. In
the presence o O2, HIF-1α is hydroxylated at a key pro-
line, allowing HIF-1α to be ubiquitinated and degraded
via the proteasome pathway. I O2 becomes limiting,
this critical hydroxylation step does not occur, allowing
HIF-1α to partner with other proteins, translocate to
the nucleus, and upregulate the expression o the EPO
gene, among others.
Impaired O2 delivery to the kidney can result rom
a decreased red cell mass (anemia), impaired O2 load-
ing o the hemoglobin molecule or a high O2 a nity
mutant hemoglobin (hypoxemia), or, rarely, impaired
blood ow to the kidney (renal artery stenosis). EPO
governs the day-to-day production o red cells, and
ambient levels o the hormone can be measured in the
plasma by sensitive immunoassays—the normal level
 an adequate supply o substrates or hemoglobin syn- 11
Iron fola te B12 thesis. A de ect in any o these key components can lead
Erythroid
ma rrow
to anemia. Generally, anemia is recognized in the labo-
Re d ce ll ma s s
Re d ce ll ratory when a patient’s hemoglobin level or hematocrit
de s truction is reduced below an expected value (the normal range).
Erythropoie tin
P la s ma T e likelihood and severity o anemia are de ned based
volume
on the deviation o the patient’s hemoglobin/hematocrit
Hb Conce ntra tion
Kidney
rom values expected or age- and sex-matched normal
tis s ue subjects. T e hemoglobin concentration in adults has a
Gaussian distribution. T e mean hematocrit value or

C
O 2 Cons umption He a rt

H
P O2
adult males is 47% (standard deviation, ±7%) and that

A
P
or adult emales is 42% (±5%). Any single hematocrit

T
E
Lungs

R
Ve s s e ls or hemoglobin value carries with it a likelihood o asso-

2
Atmos phe ric O 2 leve ls
ciated anemia. T us, a hematocrit o <39% in an adult
male or <35% in an adult emale has only about a 25%
FIGURE 2 -1
chance o being normal. Hematocrit levels are less use-

A
n
Th e p hysio lo g ic re g u la tio n o re d ce ll p ro d u ctio n b y tissu e

e
ul than hemoglobin levels in assessing anemia because

m
oxyg e n te n sio n . Hb, hemoglobin.

i
they are calculated rather than measured directly. Sus-

a
a
n
pected low hemoglobin or hematocrit values are more

d
P
being 10–25 U/L. When the hemoglobin concentration easily interpreted i previous values or the same patient

o
l
y
are known or comparison. T e World Health Organi-

c
alls below 100–120 g/L (10–12 g/dL), plasma EPO levels

y
t
h
increase in proportion to the severity o the anemia zation (WHO) de nes anemia as a hemoglobin level

e
m
(Fig. 2-2). In circulation, EPO has a hal -clearance time <130 g/L (13 g/dL) in men and <120 g/L (12 g/dL) in

i
a
o 6–9 h. EPO acts by binding to speci c receptors on women.
the sur ace o marrow erythroid precursors, inducing T e critical elements o erythropoiesis—EPO pro-
them to proli erate and to mature. With EPO stimula- duction, iron availability, the proli erative capacity o
tion, red cell production can increase our- to ve old the bone marrow, and e ective maturation o red cell
within a 1- to 2-week period, but only in the presence precursors—are used or the initial classi cation o anemia
o adequate nutrients, especially iron. T e unctional (see below).
capacity o the erythron, there ore, requires normal renal
production o EPO, a unctioning erythroid marrow, and
ANEMIA
CLINICAL PRESENTATION OF ANEMIA
10 4
Sig n s a n d sym p to m s
)
L
m
/
U
Anemia is most of en recognized by abnormal screening
m
(
10 3 laboratory tests. Patients less commonly present with
n
i
t
advanced anemia and its attendant signs and symptoms.
e
i
o
p
Acute anemia is due to blood loss or hemolysis. I blood
o
r
h
loss is mild, enhanced O2 delivery is achieved through
yt
10 2
r
e
changes in the O2–hemoglobin dissociation curve medi-
m
Norma l 9–26 mU/mL
u
ated by a decreased pH or increased CO2 (Bohr ef ect).
r
e
S
10 1 With acute blood loss, hypovolemia dominates the
clinical picture, and the hematocrit and hemoglobin
3 6 9 12 15 levels do not re ect the volume o blood lost. Signs o
He moglobin (g/dL) vascular instability appear with acute losses o 10–15%
FIGURE 2 -2 o the total blood volume. In such patients, the issue is
Eryt h ro p o ie t in (EPO) le ve ls in re sp o n se t o a n e m ia . When not anemia but hypotension and decreased organ per-
the hemoglobin level alls to 120 g/L (12 g/dL), plasma EPO lev- usion. When >30% o the blood volume is lost sud-
els increase logarithmically. In the presence o chronic kidney dis- denly, patients are unable to compensate with the
ease or chronic in ammation, EPO levels are typically lower than usual mechanisms o vascular contraction and changes
expected or the degree o anemia. As individuals age, the level in regional blood ow. T e patient pre ers to remain
o EPO needed to sustain normal hemoglobin levels appears to supine and will show postural hypotension and tachy-
increase. (From RS Hillman et al: Hematology in Clinical Practice, cardia. I the volume o blood lost is >40% (i.e., >2 L in
5th ed. New York, McGraw-Hill, 2010.) the average-sized adult), signs o hypovolemic shock
12 including con usion, dyspnea, diaphoresis, hypotension, Glucose-6-phosphate dehydrogenase (G6PD) de ciency
and tachycardia appear (Chap. 10). Such patients have and certain hemoglobinopathies are seen more commonly
signi cant de cits in vital organ per usion and require in those o Middle Eastern or A rican origin, including
immediate volume replacement. A rican Americans who have a high requency o G6PD
With acute hemolysis, the signs and symptoms de ciency. Other in ormation that may be use ul includes
depend on the mechanism that leads to red cell destruc- exposure to certain toxic agents or drugs and symptoms
tion. Intravascular hemolysis with release o ree hemo- related to other disorders commonly associated with ane-
globin may be associated with acute back pain, ree mia. T ese include symptoms and signs such as bleeding,
hemoglobin in the plasma and urine, and renal ailure. atigue, malaise, ever, weight loss, night sweats, and other
Symptoms associated with more chronic or progres-
S
systemic symptoms. Clues to the mechanisms o anemia
E
sive anemia depend on the age o the patient and the
C
may be provided on physical examination by ndings o
T
I
adequacy o blood supply to critical organs. Symptoms
O
in ection, blood in the stool, lymphadenopathy, spleno-
N
associated with moderate anemia include atigue, loss
I
megaly, or petechiae. Splenomegaly and lymphadenopa-
I
o stamina, breathlessness, and tachycardia (particu- thy suggest an underlying lymphoproli erative disease,
larly with physical exertion). However, because o the whereas petechiae suggest platelet dys unction. Past labo-
intrinsic compensatory mechanisms that govern the
C
ratory measurements are help ul to determine a time o
a
r
O2–hemoglobin dissociation curve, the gradual onset
d
i
onset.
n
o anemia—particularly in young patients—may not
a
l
In the anemic patient, physical examination may dem-
M
be associated with signs or symptoms until the anemia
a
onstrate a orce ul heartbeat, strong peripheral pulses, and
n
is severe (hemoglobin <70–80 g/L [7–8 g/dL]). When
i
f
e
a systolic “ ow” murmur. T e skin and mucous mem-
s
anemia develops over a period o days or weeks, the
t
a
branes may be pale i the hemoglobin is <80–100 g/L
t
i
total blood volume is normal to slightly increased, and
o
n
(8–10 g/dL). T is part o the physical examination should
s
changes in cardiac output and regional blood ow help
o
ocus on areas where vessels are close to the sur ace such
f
compensate or the overall loss in O2-carrying capacity.
H
e
as the mucous membranes, nail beds, and palmar creases.
m
Changes in the position o the O 2–hemoglobin dis-
a
I the palmar creases are lighter in color than the sur-
t
o
sociation curve account or some o the compensatory
l
rounding skin when the hand is hyperextended, the
o
g
response to anemia. With chronic anemia, intracellular
i
c
hemoglobin level is usually <80 g/L (8 g/dL).
D
levels o 2,3-bisphosphoglycerate rise, shif ing the dis-
i
s
e
sociation curve to the right and acilitating O2 unload- LABORATORYEVALUATION Table 2-1 lists the tests used in the
a
s
e
ing. T is compensatory mechanism can only maintain initial workup o anemia. A routine complete blood count
normal tissue O2 delivery in the ace o a 20–30 g/L (CBC) is required as part o the evaluation and includes
(2–3 g/dL) de cit in hemoglobin concentration. Finally, the hemoglobin, hematocrit, and red cell indices: the mean
urther protection o O2 delivery to vital organs is cell volume (MCV) in emtoliters, mean cell hemoglobin
achieved by the shunting o blood away rom organs (MCH) in picograms per cell, and mean concentration o
that are relatively rich in blood supply, particularly the hemoglobin per volume o red cells (MCHC) in grams per
kidney, gut, and skin. liter (non-SI: grams per deciliter). T e red cell indices are
Certain disorders are commonly associated with ane- calculated as shown in Table 2-2, and the normal variations
mia. Chronic in ammatory states (e.g., in ection, rheu- in the hemoglobin and hematocrit with age are shown in
matoid arthritis, cancer) are associated with mild to Table 2-3. A number o physiologic actors a ect the CBC,
moderate anemia, whereas lymphoproli erative disor- including age, sex, pregnancy, smoking, and altitude.
ders, such as chronic lymphocytic leukemia and certain High-normal hemoglobin values may be seen in men and
other B cell neoplasms, may be associated with auto- women who live at altitude or smoke heavily. Hemoglobin
immune hemolysis. elevations due to smoking re ect normal compensation
due to the displacement o O2 by CO in hemoglobin bind-
ing. Other important in ormation is provided by the retic-
ulocyte count and measurements o iron supply including
APPROACHTOTHEPATIENT: serum iron, total iron-binding capacity ( IBC; an indirect
Anemia measure o serum trans errin), and serum erritin. Marked
T e evaluation o the patient with anemia requires a alterations in the red cell indices usually re ect disorders o
care ul history and physical examination. Nutritional maturation or iron de ciency. A care ul evaluation o the
history related to drugs or alcohol intake and amily his- peripheral blood smear is important, and clinical laborato-
tory o anemia should always be assessed. Certain geo- ries of en provide a description o both the red and white
graphic backgrounds and ethnic origins are associated cells, a white cell di erential count, and the platelet count.
with an increased likelihood o an inherited disorder o In patients with severe anemia and abnormalities in red
the hemoglobin molecule or intermediary metabolism. blood cell morphology and/or low reticulocyte counts, a
TABLE 2 -1 TABLE 2 -3 13
LABORATORY TESTS IN ANEMIA DIAGNOSIS CHANGES IN NORMAL HEMOGLOBIN/HEMATOCRIT
I. Complete blood count (CBC) VALUES WITH AGE, SEX, AND PREGNANCY
A. Red blood cell count AGE/SEX HEMOGLOBIN, g /d L HEMATOCRIT, %
1. Hemoglobin
2. Hematocrit At birth 17 52
3. Reticulocyte count Childhood 12 36
B. Red blood cell indices Adolescence 13 40
1. Mean cell volume (MCV)
Adult man 16 (±2) 47 (±6)
2. Mean cell hemoglobin (MCH)
Adult woman 13 (±2) 40 (±6)

C
3. Mean cell hemoglobin concentration (MCHC)

H
(menstruating)

A
4. Red cell distribution width (RDW)

P
C. White blood cell count

T
Adult woman 14 (±2) 42 (±6)

E
R
1. Cell di erential (postmenopausal)

2
2. Nuclear segmentation o neutrophils During pregnancy 12 (±2) 37 (±6)
D. Platelet count
E. Cell morphology
So u rce : From RS Hillman et al: Hematology in Clinical Practice, 5th ed.

A
1. Cell size

n
New York, McGraw-Hill, 2010.

e
m
2. Hemoglobin content

i
a
3. Anisocytosis

a
n
4. Poikilocytosis hemoglobin synthesis (hypochromia). Automated cell coun-

d
P
5. Polychromasia ters describe the red cell volume distribution width (RDW).

o
l
y
II. Iron supply studies T e MCV (representing the peak o the distribution curve)

c
y
t
A. Serum iron

h
is insensitive to the appearance o small populations o

e
B. Total iron-binding capacity

m
macrocytes or microcytes. An experienced laboratory

i
a
C. Serum erritin
III. Marrow examination technician will be able to identi y minor populations o
A. Aspirate large or small cells or hypochromic cells be ore the red cell
1. M/E ratio a indices change.
2. Cell morphology
3. Iron stain Peripheral Blood Smear he peripheral blood smear pro-
B. Biopsy vides important in ormation about de ects in red cell
1. Cellularity production (Chap. 6). As a complement to the red cell
2. Morphology indices, the blood smear also reveals variations in cell size
(anisocytosis) and shape (poikilocytosis). he degree o
a
M/E ratio, ratio o myeloid to erythroid precursors. anisocytosis usually correlates with increases in the RDW
or the range o cell sizes. Poikilocytosis suggests a de ect
in the maturation o red cell precursors in the bone mar-
bone marrow aspirate or biopsy can assist in the diagnosis. row or ragmentation o circulating red cells. he blood
Other tests o value in the diagnosis o speci c anemias are smear may also reveal polychromasia—red cells that are
discussed in chapters on speci c disease states. slightly larger than normal and grayish blue in color on
T e components o the CBC also help in the classi ca- the Wright-Giemsa stain. hese cells are reticulocytes that
tion o anemia. Microcytosis is re ected by a lower than have been prematurely released rom the bone marrow,
normal MCV (<80), whereas high values (>100) re ect and their color represents residual amounts o ribosomal
macrocytosis. T e MCH and MCHC re ect de ects in RNA. hese cells appear in circulation in response to EPO
stimulation or to architectural damage o the bone marrow
( ibrosis, in iltration o the marrow by malignant cells, etc.)
that results in their disordered release rom the marrow.
TABLE 2 -2
he appearance o nucleated red cells, Howell-Jolly bodies,
RED BLOOD CELL INDICES
target cells, sickle cells, and others may provide clues to
INDEX NORMAL VALUE speci ic disorders (Figs. 2-3 to 2-11).
Mean cell volume (MCV) = (hematocrit × 90 ± 8 L Reticulocyte Count An accurate reticulocyte count is key to
10)/(red cell count × 106)
the initial classi cation o anemia. Reticulocytes are red
Mean cell hemoglobin (MCH) = 30 ± 3 pg cells that have been recently released rom the bone mar-
(hemoglobin × 10)/(red cell count × 106) row. T ey are identi ed by staining with a supravital dye
Mean cell hemoglobin concentration = 33 ± 2% that precipitates the ribosomal RNA (Fig. 2-12). T ese
(hemoglobin × 10)/hematocrit, or precipitates appear as blue or black punctate spots and can
MCH/MCV
be counted manually or, currently, by uorescent emission
14
S
E
C
T
I
O
N
I
I
FIGURE 2 -3 FIGURE 2 -6
No rm a l b lo o d sm e ar (Wrig ht sta in ). High-power f eld show- Ho we ll-Jo lly b o d ie s. In the absence o a unctional spleen,
C
a
ing normal red cells, a neutrophil, and a ew platelets. (From RS nuclear remnants are not culled rom the red cells and remain as
r
d
i
n
Hillman et al: Hematology in Clinical Practice, 5th ed. New York, small homogeneously staining blue inclusions on Wright stain.
a
l
McGraw-Hill, 2010.) (From RS Hillman et al: Hematology in Clinical Practice, 5th ed.
M
a
New York, McGraw-Hill, 2010.)
n
i
f
e
s
t
a
t
i
o
n
s
o
f
H
e
m
a
t
o
l
o
g
i
c
D
i
s
e
a
s
e
FIGURE 2 -4
Se ve re iro n -d e cie n cy a n e m ia . Microcytic and hypochromic FIGURE 2 -7
red cells smaller than the nucleus o a lymphocyte associated with Red cell changes in myelo b rosis. The le t panel shows a teardrop-
marked variation in size (anisocytosis) and shape (poikilocytosis). shaped cell. The right panel shows a nucleated red cell. These orms
(From RS Hillman et al: Hematology in Clinical Practice, 5th ed. can be seen in myelof brosis.
New York, McGraw-Hill, 2010.)

FIGURE 2 -8
FIGURE 2 -5 Ta rg e t ce lls. Target cells have a bull’s-eye appearance and are
Macrocytosis. Red cells are larger than a small lymphocyte and well seen in thalassemia and in liver disease. (From RS Hillman et al:
hemoglobinized. O ten macrocytes are oval shaped (macro-ovalocytes). Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.)

FIGURE 2 -9
Re d ce ll ra g m e n t a t io n . Red cells may become ragmented
FIGURE 2 -1 2
in the presence o oreign bodies in the circulation, such as
Re t icu lo cyt e s. Methylene blue stain demonstrates residual RNA
mechanical heart valves, or in the setting o thermal injury. (From
in newly made red cells. (From RS Hillman et al: Hematology in
RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York,
Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.)
McGraw-Hill, 2010.)
FIGURE 2 -1 0
Ure m ia . The red cells in uremia may acquire numerous regu-
larly spaced, small, spiny projections. Such cells, called burr cells
or echinocytes, are readily distinguishable rom irregularly spicu-
lated acanthocytes shown in Fig. 2-11.
FIGURE 2 -1 1
Sp u r ce lls. Spur cells are recognized as distorted red cells con-
taining several irregularly distributed thornlike projections. Cells
with this morphologic abnormality are also called acanthocytes.
(From RS Hillman et al: Hematology in Clinical Practice, 5th ed.
New York, McGraw-Hill, 2010.)
15
C
H
A
P
T
E
R
2
A
n
e
m
i
a
a
n
d
P
o
l
y
c
y
o dyes that bind to RNA. T is residual RNA is metabo-
t
h
e
lized over the rst 24–36 h o the reticulocyte’s li e span in
m
i
circulation. Normally, the reticulocyte count ranges rom
a
1 to 2% and re ects the daily replacement o 0.8–1.0% o
the circulating red cell population. A corrected reticulo-
cyte count provides a reliable measure o e ective red cell
production.
In the initial classi cation o anemia, the patient’s retic-
ulocyte count is compared with the expected reticulocyte
response. In general, i the EPO and erythroid marrow
responses to moderate anemia [hemoglobin <100 g/L
(10 g/dL)] are intact, the red cell production rate increases
to two to three times normal within 10 days ollowing
the onset o anemia. In the ace o established anemia, a
reticulocyte response less than two to three times normal
indicates an inadequate marrow response.
o use the reticulocyte count to estimate marrow
response, two corrections are necessary. T e rst correc-
tion adjusts the reticulocyte count based on the reduced
number o circulating red cells. With anemia, the percent-
age o reticulocytes may be increased while the absolute
number is unchanged. o correct or this e ect, the reticu-
locyte percentage is multiplied by the ratio o the patient’s
hemoglobin or hematocrit to the expected hemoglobin/
hematocrit or the age and sex o the patient (Table 2-4).
T is provides an estimate o the reticulocyte count cor-
rected or anemia. o convert the corrected reticulocyte
count to an index o marrow production, a urther correc-
tion is required, depending on whether some o the reticu-
locytes in circulation have been released rom the marrow
prematurely. For this second correction, the peripheral
blood smear is examined to see i there are polychromato-
philic macrocytes present.
T ese cells, representing prematurely released reticu-
locytes, are re erred to as “shif ” cells, and the relationship
16 TABLE 2 -4 TABLE 2 -5
CALCULATION OF RETICULOCYTE PRODUCTION NORMAL MARROW RESPONSE TO ANEMIA
INDEX
PRODUCTION RETICULOCYTE
Correction #1 for Anemia: HEMOGLOBIN INDEX COUNT
This correction produces the corrected reticulocyte count.
15 g/dL 1 50,000/µL
In a person whose reticulocyte count is 9%, hemoglobin 7.5 g/dL,
and hematocrit 23%, the absolute reticulocyte count = 11 g/dL 2.0–2.5 100–150,000/µL
9 × (7.5/15) [or × (23/45)] = 4.5% 8 g/dL 3.0–4.0 300–400,000/µL
Note. This correction is not done i the reticulocyte count is
reported in absolute numbers (e.g., 50,000/µL o blood)
S
Correction #2 for Longer Life of Prematurely Released
E
severity o anemia. In general, a correction o 2 is simply
C
Reticulocytes in the Blood:
T
I
used. An appropriate correction is shown in able 2-4. I
O
This correction produces the reticulocyte production index.
N
In a person whose reticulocyte count is 9%, hemoglobin polychromatophilic cells are not seen on the blood smear,
I
I
7.5 gm/dL, and hematocrit 23%, the reticulocyte the second correction is not required. T e now doubly
production index corrected reticulocyte count is the reticulocyte production
index, and it provides an estimate o marrow production
C
(7.5 / 15)(hemoglobin correction)
a
=9× = 2.25
r
relative to normal. In many hospital laboratories, the retic-
d
2(maturation time correction)
i
n
ulocyte count is reported not only as a percentage but also
a
l
M
in absolute numbers. I so, no correction or dilution is
a
n
required. A summary o the appropriate marrow response
i
f
between the degree o shif and the necessary shif correc-
e
s
to varying degrees o anemia is shown in Table 2-5.
t
a
tion actor is shown in Fig. 2-13. T e correction is neces-
t
i
Premature release o reticulocytes is normally due to
o
sary because these prematurely released cells survive as
n
s
increased EPO stimulation. However, i the integrity o
o
reticulocytes in circulation or >1 day, thereby providing a
f
H
alsely high estimate o daily red cell production. I poly- the bone marrow release process is lost through tumor
e
m
in ltration, brosis, or other disorders, the appearance
a
chromasia is increased, the reticulocyte count, already cor-
t
o
o nucleated red cells or polychromatophilic macrocytes
l
rected or anemia, should be divided again by 2 to account
o
g
should still invoke the second reticulocyte correction.
i
or the prolonged reticulocyte maturation time. T e sec-
c
D
T e shif correction should always be applied to a patient
i
ond correction actor varies rom 1 to 3 depending on the
s
e
with anemia and a very high reticulocyte count to pro-
a
s
e
vide a true index o e ective red cell production. Patients
Marrow Pe riphe ral
no rmo blas ts and blo o d with severe chronic hemolytic anemia may increase red
re tic ulo c yte s re tic ulo c yte s cell production as much as six- to seven old. T is measure
He mato c rit (%) (days ) (days ) alone con rms the act that the patient has an appropri-
45 3.5 1.0 ate EPO response, a normally unctioning bone marrow,
and su cient iron available to meet the demands or new
35 3.0 1.5 red cell ormation. I the reticulocyte production index is
<2 in the ace o established anemia, a de ect in erythroid
25 2.5 2.0
marrow proli eration or maturation must be present.
15 1.5 2.5 Tests of Iron Supply and Storage T e laboratory measure-
ments that re ect the availability o iron or hemoglobin
“S HIFT”
synthesis include the serum iron, the IBC, and the
corre ction fa ctor percent trans errin saturation. T e percent trans errin
saturation is derived by dividing the serum iron level
FIGURE 2 -1 3 (× 100) by the IBC. T e normal serum iron ranges rom 9
Co rre ct io n o t h e re t icu lo cyt e co u n t. To use the reticulocyte to 27 µmol/L (50–150 µg/dL), whereas the normal IBC is
count as an indicator o e ective red cell production, the reticulo- 54–64 µmol/L (300–360 µg/dL); the normal trans errin sat-
cyte percentage must be corrected based on the level o anemia uration ranges rom 25 to 50%. A diurnal variation in the
and the circulating li e span o the reticulocytes. Erythroid cells serum iron leads to a variation in the percent trans errin
take ~4.5 days to mature. At a normal hemoglobin, reticulocytes
saturation. T e serum erritin is used to evaluate total body
are released to the circulation with ~1 day le t as reticulocytes.
iron stores. Adult males have serum erritin levels that
However, with di erent levels o anemia, reticulocytes (and even
average ~100 µg/L, corresponding to iron stores o ~1 g.
earlier erythroid cells) may be released rom the marrow prema-
Adult emales have lower serum erritin levels averaging
turely. Most patients come to clinical attention with hematocrits
30 µg/L, re ecting lower iron stores (~300 mg). A serum
in the mid-20s, and thus a correction actor o 2 is commonly
used because the observed reticulocytes will live or 2 days in the
erritin level o 10–15 µg/L indicates depletion o body iron
circulation be ore losing their RNA. stores. However, erritin is also an acute-phase reactant

FIGURE 2 -1 4
No rm a l b o n e m a rro w. This is a low-power view o a section o
a normal bone marrow biopsy stained with hematoxylin and
eosin (H&E). Note that the nucleated cellular elements account
or ~40–50% and the at (clear areas) accounts or ~50–60% o the
area. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed.
New York, McGraw-Hill, 2010.)
and, in the presence o acute or chronic in ammation, may
rise several- old above baseline levels. As a rule, a serum
erritin >200 µg/L means there is at least some iron in tis-
sue stores.
Bone Marrow Examination A bone marrow aspirate and smear
or a needle biopsy can be use ul in the evaluation o some
patients with anemia. In patients with hypoproli erative
anemia and normal iron status, a bone marrow is indicated.
Marrow examination can diagnose primary marrow dis-
orders such as myelo brosis, a red cell maturation de ect,
or an in ltrative disease (Figs. 2-14 to 2-16). T e increase
or decrease o one cell lineage (myeloid vs erythroid)
FIGURE 2 -1 5
Eryth ro id hyp e rp la sia . This marrow shows an increase in the
raction o cells in the erythroid lineage as might be seen when a
normal marrow compensates or acute blood loss or hemolysis. The
myeloid/erythroid (M/E) ratio is about 1:1. (From RS Hillman et al:
Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.)
17
C
H
A
P
T
E
R
2
FIGURE 2 -1 6
Mye lo id h yp e rp la sia . This marrow shows an increase in
A
n
the raction o cells in the myeloid or granulocytic lineage as
e
m
might be seen in a normal marrow responding to in ection. The
i
a
a
myeloid/erythroid (M/E) ratio is >3:1. (From RS Hillman et al: Hema-
n
d
tology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.)
P
o
l
y
c
y
t
compared to another is obtained by a di erential count
h
e
m
o nucleated cells in a bone marrow smear (the myeloid/
i
a
erythroid [M/E] ratio). A patient with a hypoproli erative
anemia (see below) and a reticulocyte production index
<2 will demonstrate an M/E ratio o 2 or 3:1. In contrast,
patients with hemolytic disease and a production index >3
will have an M/E ratio o at least 1:1. Maturation disorders
are identi ed rom the discrepancy between the M/E ratio
and the reticulocyte production index (see below). Either
the marrow smear or biopsy can be stained or the presence
o iron stores or iron in developing red cells. T e storage
iron is in the orm o erritin or hemosiderin. On care ully
prepared bone marrow smears, small erritin granules can
normally be seen under oil immersion in 20–40% o devel-
oping erythroblasts. Such cells are called sideroblasts.
OTHER LABORATORY MEASUREMENTS Additional laboratory
tests may be o value in con rming speci c diagnoses. For
details of these tests and how they are applied in indi-
vidual disorders, see Chaps. 7 to 11.
DEFINITION AND CLASSIFICATION OF
ANEMIA
In itia l cla ssif ca tio n o a n em ia
T e unctional classi cation o anemia has three major
categories. T ese are (1) marrow production de ects
(hypoproli eration), (2) red cell maturation de ects (ine -
ective erythropoiesis), and (3) decreased red cell sur-
vival (blood loss/hemolysis). T e classi cation is shown
in Fig. 2-17. A hypoproli erative anemia is typically
seen with a low reticulocyte production index together
with little or no change in red cell morphology (a nor-
mocytic, normochromic anemia) (Chap. 7). Maturation
disorders typically have a slight to moderately elevated
18 ALGORITHM OF THE P HYS IOLOGIC CLAS S IFICATION OF ANEMIA Hyp o p ro li era tive a n em ia s
Ane mia At least 75% o all cases o anemia are hypoproli -
erative in nature. A hypoproli erative anemia re ects
absolute or relative marrow ailure in which the ery-
CBC, re ticulocyte
count throid marrow has not proli erated appropriately or
the degree o anemia. T e majority o hypoproli era-
tive anemias are due to mild to moderate iron de -
Index < 2.5 Index ≥ 2.5
ciency or in ammation. A hypoproli erative anemia
can result rom marrow damage, iron de ciency, or
S
Re d ce ll He molys is / inadequate EPO stimulation. T e last may re ect
E
C
morphology he morrha ge
impaired renal unction, suppression o EPO produc-
T
I
O
Blood los s
tion by in ammatory cytokines such as interleukin
N
Normocytic Micro or
I
1, or reduced tissue needs or O 2 rom metabolic dis-
I
normochromic ma crocytic Intrava s cula r
he molys is
ease such as hypothyroidism. Only occasionally is the
Me ta bolic de fe ct marrow unable to produce red cells at a normal rate,
C
Hypoprolife ra tive Ma tura tion dis orde r
and this is most prevalent in patients with renal ail-
a
Me mbra ne
r
d
a bnorma lity
i
ure. With diabetes mellitus or myeloma, the EPO de -
n
Ma rrow da ma ge Cytopla s mic de fe cts
a
l
• Infiltra tion/fibros is • Iron de ficie ncy He moglobinopa thy ciency may be more marked than would be predicted
M
• Apla s ia • Tha la s s e mia
a
by the degree o renal insu ciency. In general, hypo-
n
Iron de ficie ncy • S ide robla s tic Immune de s truction
i
f
a ne mia
e
proli erative anemias are characterized by normocytic,
s
S timula tion Fra gme nta tion
t
a
• Infla mma tion Nucle a r de fe cts normochromic red cells, although microcytic, hypo-
t
he molys is
i
o
• Me ta bolic de fe ct • Fola te de ficie ncy
n
• Re na l dis e a s e • Vita min B 12 de ficie ncy chromic cells may be observed with mild iron de -
s
o
• Drug toxicity
ciency or long-standing chronic in ammatory disease.
f
H
• Re fra ctory a ne mia
e
T e key laboratory tests in distinguishing between the
m
a
various orms o hypoproli erative anemia include the
t
o
FIGURE 2 -1 7
l
serum iron and iron-binding capacity, evaluation o
o
g
Th e p hysio lo g ic cla ssi ca tio n o a n e m ia . CBC, complete blood
i
c
renal and thyroid unction, a marrow biopsy or aspi-
D
count.
i
rate to detect marrow damage or in ltrative disease,
s
e
a
s
and serum erritin to assess iron stores. An iron stain
e
reticulocyte production index that is accompanied by
either macrocytic (Chap. 9) or microcytic (Chaps. 7, 8) o the marrow will determine the pattern o iron dis-
red cell indices. Increased red blood cell destruction tribution. Patients with the anemia o acute or chronic
secondary to hemolysis results in an increase in the in ammation show a distinctive pattern o serum
reticulocyte production index to at least three times iron (low), IBC (normal or low), percent trans er-
normal (Chap. 10), provided su cient iron is avail- rin saturation (low), and serum erritin (normal or
able. Hemorrhagic anemia does not typically result in high). T ese changes in iron values are brought about
production indices o more than 2.0–2.5 times normal by hepcidin, the iron regulatory hormone that is pro-
because o the limitations placed on expansion o the duced by the liver and is increased in in ammation
erythroid marrow by iron availability. (Chap. 7). A distinct pattern o results is noted in mild
In the rst branch point o the classi cation o ane- to moderate iron de ciency (low serum iron, high
mia, a reticulocyte production index >2.5 indicates IBC, low percent trans errin saturation, low serum
that hemolysis is most likely. A reticulocyte production erritin) (Chap. 7). Marrow damage by drugs, in ltra-
index <2 indicates either a hypoproli erative anemia tive disease such as leukemia or lymphoma, or marrow
or maturation disorder. T e latter two possibilities can aplasia is diagnosed rom the peripheral blood and
of en be distinguished by the red cell indices, by exami- bone marrow morphology. With in ltrative disease or
nation o the peripheral blood smear, or by a marrow brosis, a marrow biopsy is required.
examination. I the red cell indices are normal, the
anemia is almost certainly hypoproli erative in nature. Ma tura tio n d iso rd ers
Maturation disorders are characterized by ine ective
red cell production and a low reticulocyte production T e presence o anemia with an inappropriately low
index. Bizarre red cell shapes—macrocytes or hypo- reticulocyte production index, macro- or microcytosis
chromic microcytes—are seen on the peripheral blood on smear, and abnormal red cell indices suggests a mat-
smear. With a hypoproli erative anemia, no erythroid uration disorder. Maturation disorders are divided into
hyperplasia is noted in the marrow, whereas patients two categories: nuclear maturation de ects, associated
with ine ective red cell production have erythroid with macrocytosis, and cytoplasmic maturation de ects,
hyperplasia and an M/E ratio <1:1. associated with microcytosis and hypochromia usually
 rom de ects in hemoglobin synthesis. T e inappropri-
ately low reticulocyte production index is a re ection
o the ine ective erythropoiesis that results rom the
destruction within the marrow o developing eryth-
roblasts. Bone marrow examination shows erythroid
hyperplasia.
Nuclear maturation de ects result rom vitamin
B12 or olic acid de ciency, drug damage, or myelo-
dysplasia. Drugs that inter ere with cellular DNA syn-
thesis, such as methotrexate or alkylating agents, can
produce a nuclear maturation de ect. Alcohol, alone, is
also capable o producing macrocytosis and a variable
degree o anemia, but this is usually associated with
olic acid de ciency. Measurements o olic acid and
vitamin B12 are critical not only in identi ying the spe-
ci c vitamin de ciency but also because they re ect di -
erent pathogenetic mechanisms (Chap. 9).
Cytoplasmic maturation de ects result rom severe
iron de ciency or abnormalities in globin or heme syn-
thesis. Iron de ciency occupies an unusual position
in the classi cation o anemia. I the iron-de ciency
anemia is mild to moderate, erythroid marrow proli -
eration is blunted and the anemia is classi ed as hypo-
proli erative. However, i the anemia is severe and
prolonged, the erythroid marrow will become hyper-
plastic despite the inadequate iron supply, and the ane-
mia will be classi ed as ine ective erythropoiesis with a
cytoplasmic maturation de ect. In either case, an inap-
propriately low reticulocyte production index, micro-
cytosis, and a classic pattern o iron values make the
diagnosis clear and easily distinguish iron de ciency
rom other cytoplasmic maturation de ects such as the
thalassemias. De ects in heme synthesis, in contrast to
globin synthesis, are less common and may be acquired
or inherited. Acquired abnormalities are usually associ-
ated with myelodysplasia, may lead to either a macro-
or microcytic anemia, and are requently associated
with mitochondrial iron loading. In these cases, iron
is taken up by the mitochondria o the developing ery-
throid cell but not incorporated into heme. T e iron-
encrusted mitochondria surround the nucleus o the
erythroid cell, orming a ring. Based on the distinctive
nding o so-called ringed sideroblasts on the marrow
iron stain, patients are diagnosed as having a sidero-
blastic anemia—almost always re ecting myelodyspla-
sia. Again, studies o iron parameters are help ul in the
di erential diagnosis o these patients.
Blo o d lo ss/h em o lytic a n em ia
In contrast to anemias associated with an inappropri-
ately low reticulocyte production index, hemolysis is
associated with red cell production indices ≥2.5 times
normal. T e stimulated erythropoiesis is re ected in the
blood smear by the appearance o increased numbers
o polychromatophilic macrocytes. A marrow exami- 19
nation is rarely indicated i the reticulocyte production
index is increased appropriately. T e red cell indices are
typically normocytic or slightly macrocytic, re ecting
the increased number o reticulocytes. Acute blood loss
is not associated with an increased reticulocyte produc-
tion index because o the time required to increase EPO
production and, subsequently, marrow proli eration.
Subacute blood loss may be associated with modest
reticulocytosis. Anemia rom chronic blood loss pres-
C
H
ents more of en as iron de ciency than with the picture
A
P
T
o increased red cell production.
E
R
T e evaluation o blood loss anemia is usually not di -
2
cult. Most problems arise when a patient presents with
an increased red cell production index rom an episode
A
o acute blood loss that went unrecognized. T e cause o
n
e
the anemia and increased red cell production may not
m
i
a
be obvious. T e con rmation o a recovering state may
a
n
require observations over a period o 2–3 weeks, during
d
P
o
which the hemoglobin concentration will rise and the
l
y
c
reticulocyte production index all (Chap. 10).
y
t
h
Hemolytic disease, while dramatic, is among the least
e
m
i
common orms o anemia. T e ability to sustain a high
a
reticulocyte production index re ects the ability o the
erythroid marrow to compensate or hemolysis and, in
the case o extravascular hemolysis, the e cient recy-
cling o iron rom the destroyed red cells to support red
cell production. With intravascular hemolysis, such as
paroxysmal nocturnal hemoglobinuria, the loss o iron
may limit the marrow response. T e level o response
depends on the severity o the anemia and the nature o
the underlying disease process.
Hemoglobinopathies, such as sickle cell disease and
the thalassemias, present a mixed picture. T e reticu-
locyte index may be high but is inappropriately low or
the degree o marrow erythroid hyperplasia (Chap. 8).
Hemolytic anemias present in di erent ways. Some
appear suddenly as an acute, sel -limited episode o
intravascular or extravascular hemolysis, a presentation
pattern of en seen in patients with autoimmune hemo-
lysis or with inherited de ects o the Embden-Meyerho
pathway or the glutathione reductase pathway. Patients
with inherited disorders o the hemoglobin molecule or
red cell membrane generally have a li elong clinical his-
tory typical o the disease process. T ose with chronic
hemolytic disease, such as hereditary spherocytosis,
may actually present not with anemia but with a com-
plication stemming rom the prolonged increase in red
cell destruction such as symptomatic bilirubin gall-
stones or splenomegaly. Patients with chronic hemoly-
sis are also susceptible to aplastic crises i an in ectious
process interrupts red cell production.
T e di erential diagnosis o an acute or chronic
hemolytic event requires the care ul integration o
amily history, the pattern o clinical presentation,
20 and—whether the disease is congenital or acquired— Of en patients with polycythemia are detected through
care ul examination o the peripheral blood smear. Pre- an incidental nding o elevated hemoglobin or hema-
cise diagnosis may require more specialized laboratory tocrit levels. Concern that the hemoglobin level may
tests, such as hemoglobin electrophoresis or a screen be abnormally high is usually triggered at 170 g/L
or red cell enzymes. Acquired de ects in red cell sur- (17 g/dL) or men and 150 g/L (15 g/dL) or women.
vival are of en immunologically mediated and require a Hematocrit levels >50% in men or >45% in women
direct or indirect antiglobulin test or a cold agglutinin may be abnormal. Hematocrits >60% in men and
titer to detect the presence o hemolytic antibodies or >55% in women are almost invariably associated with
complement-mediated red cell destruction (Chap. 10). an increased red cell mass. Given that the machine
that quantitates red cell parameters actually measures
S
E
hemoglobin concentrations and calculates hematocrits,
C
T
I
TREATMENT Anemia hemoglobin levels may be a better index.
O
N
Features o the clinical history that are use ul in the
I
I
An overriding principle is to initiate treatment o mild to di erential diagnosis include smoking history; current
moderate anemia only when a speci c diagnosis is made. living at high altitude; or a history o congenital heart
Rarely, in the acute setting, anemia may be so severe that red disease, sleep apnea, or chronic lung disease.
C
a
r
cell trans usions are required be ore a speci c diagnosis is Patients with polycythemia may be asymptomatic or
d
i
n
available. Whether the anemia is o acute or gradual onset, the experience symptoms related to the increased red cell
a
l
M
selection o the appropriate treatment is determined by the mass or the underlying disease process that leads to the
a
n
documented cause(s) o the anemia. Of en, the cause o the increased red cell mass. T e dominant symptoms rom
i
f
e
s
anemia is multi actorial. For example, a patient with severe an increased red cell mass are related to hyperviscosity
t
a
t
i
rheumatoid arthritis who has been taking anti-in ammatory and thrombosis (both venous and arterial), because the
o
n
s
drugs may have a hypoproli erative anemia associated with blood viscosity increases logarithmically at hematocrits
o
f
>55%. Mani estations range rom digital ischemia to
H
chronic in ammation as well as chronic blood loss associ-
e
m
ated with intermittent gastrointestinal bleeding. In every Budd-Chiari syndrome with hepatic vein thrombosis.
a
t
o
circumstance, it is important to evaluate the patient’s iron Abdominal vessel thromboses are particularly common.
l
o
g
status ully be ore and during the treatment o any anemia. Neurologic symptoms such as vertigo, tinnitus, head-
i
c
D
Transfusion is discussed in Chap. 12; iron therapy is dis- ache, and visual disturbances may occur. Hypertension
i
s
e
cussed in Chap. 7; treatment of megaloblastic anemia is is of en present. Patients with polycythemia vera may
a
s
e
discussed in Chap. 9; treatment of other entities is dis- have aquagenic pruritus and symptoms related to hepa-
cussed in their respective chapters (sickle cell anemia, tosplenomegaly. Patients may have easy bruising, epi-
Chap. 8; hemolytic anemias, Chap. 10; aplastic anemia and staxis, or bleeding rom the gastrointestinal tract. Peptic
myelodysplasia, Chap. 11). ulcer disease is common. Patients with hypoxemia may
T erapeutic options or the treatment o anemias have develop cyanosis on minimal exertion or have head-
expanded dramatically during the past 30 years. Blood com- ache, impaired mental acuity, and atigue.
ponent therapy is available and sa e. Recombinant EPO as an T e physical examination usually reveals a ruddy
adjunct to anemia management has trans ormed the lives o complexion. Splenomegaly avors polycythemia vera as
patients with chronic renal ailure on dialysis and reduced the diagnosis (Chap. 13). T e presence o cyanosis or
trans usion needs o anemic cancer patients receiving chemo- evidence o a right-to-lef shunt suggests congenital heart
therapy. Eventually, patients with inherited disorders o glo- disease presenting in the adult, particularly tetralogy o
bin synthesis or mutations in the globin gene, such as sickle Fallot or Eisenmenger’s syndrome. Increased blood vis-
cell disease, may bene t rom the success ul introduction o cosity raises pulmonary artery pressure; hypoxemia
targeted genetic therapy. can lead to increased pulmonary vascular resistance.
ogether, these actors can produce cor pulmonale.
Polycythemia can be spurious (related to a decrease
P O LYCYTHEMIA in plasma volume; Gaisbock’s syndrome), primary,
or secondary in origin. T e secondary causes are all
Polycythemia is de ned as an increase in the hemoglo- associated with increases in EPO levels: either a physi-
bin above normal. T is increase may be real or only ologically adapted appropriate elevation based on tis-
apparent because o a decrease in plasma volume (spu- sue hypoxia (lung disease, high altitude, CO poisoning,
rious or relative polycythemia). T e term erythrocytosis high-a nity hemoglobinopathy) or an abnormal over-
may be used interchangeably with polycythemia, but production (renal cysts, renal artery stenosis, tumors
some draw a distinction between them: erythrocytosis with ectopic EPO production). A rare amilial orm o
implies documentation o increased red cell mass, polycythemia is associated with normal EPO levels but
whereas polycythemia re ers to any increase in red cells. hyperresponsive EPO receptors due to mutations.

APPROACHTOTHEPATIENT:
Polycythemia
As shown in Fig. 2-18, the rst step is to document the
presence o an increased red cell mass using the prin-
ciple o isotope dilution by administering 51Cr-labeled
autologous red blood cells to the patient and sampling
blood radioactivity over a 2-h period. I the red cell mass
is normal (<36 mL/kg in men, <32 mL/kg in women),
21
the patient has spurious or relative polycythemia. I the
red cell mass is increased (>36 mL/kg in men, >32 mL/kg
in women), serum EPO levels should be measured. I EPO
levels are low or unmeasurable, the patient most likely
has polycythemia vera. A mutation in JAK2 (Val617Phe),
a key member o the cytokine intracellular signaling path-
way, can be ound in 90–95% o patients with polycy-
themia vera. Many o those without this particular JAK2
mutation have mutations in exon 12. As a practical matter,

C
ew centers assess red cell mass in the setting o an

H
A
increased hematocrit. T e short workup is to measure

P
T
AN APPROACH TO DIAGNOS ING P ATIENTS WITH P OLYCYTHEMIA EPO levels, check or JAK2 mutation, and per orm an

E
R
abdominal ultrasound to assess spleen size. ests that sup-

2
Incre a s e d hct or hgb

norma l port the diagnosis o polycythemia vera include elevated

Me a s ure RBC ma s s Dx: Re la tive white blood cell count, increased absolute basophil count,

A
e rythrocytos is and thrombocytosis.

n
e
e leva te d

m
I serum EPO levels are elevated, one needs to distin-

i
a
low Confirm
guish whether the elevation is a physiologic response

a
Me a s ure s e rum Dx: Polycythe mia JAK2

n
EP O leve ls

d
ve ra muta tion to hypoxia or related to autonomous EPO production.

P
o
e leva te d Patients with low arterial O2 saturation (<92%) should be

l
y
c
y
low urther evaluated or the presence o heart or lung dis-

t
Me a s ure a rte ria l

h
Dia gnos tic eva lua tion for

e
O 2 s a tura tion he a rt or lung dis e a s e, ease, i they are not living at high altitude. Patients with

m
e.g., COP D, high a ltitude,

i
a
norma l AV or intra ca rdia c s hunt normal O2 saturation who are smokers may have elevated
no EPO levels because o CO displacement o O2. I car-
s moke r? Me a s ure he moglobin boxyhemoglobin (COHb) levels are high, the diagnosis is
O 2 a ffinity
ye s
norma l
“smoker’s polycythemia.” Such patients should be urged
incre a s e d to stop smoking. T ose who cannot stop smoking require
Me a s ure norma l phlebotomy to control their polycythemia. Patients with
ca rboxyhe moglobin Dx: O 2 a ffinity
leve ls he moglobinopa thy normal O2 saturation who do not smoke either have an
abnormal hemoglobin that does not deliver O2 to the
e leva te d S e a rch for tumor a s s ource of EP O
IVP /re na l ultra s ound (re na l Ca or cys t) tissues (evaluated by nding elevated O2–hemoglobin
Dx: S moke r’s CT of he a d (ce re be lla r he ma ngioma ) a nity) or have a source o EPO production that is not
polycythe mia CT of pe lvis (ute rine le iomyoma )
CT of a bdome n (he pa toma ) responding to the normal eedback inhibition. Further
workup is dictated by the di erential diagnosis o EPO-
producing neoplasms. Hepatoma, uterine leiomyoma, and
FIGURE 2 -1 8
renal cancer or cysts are all detectable with abdominopel-
An a p p ro a ch t o t h e d if e re n t ia l d ia g n o sis o p a t ie n ts wit h
vic computed tomography scans. Cerebellar hemangiomas
a n e le va t e d h e m o g lo b in (p o ssib le p o lycyt h e m ia ). AV, atrio-
may produce EPO, but they present with localizing neu-
ventricular; COPD, chronic obstructive pulmonary disease; CT,
computed tomography; EPO, erythropoietin; hct, hematocrit; hgb, rologic signs and symptoms rather than polycythemia-
hemoglobin; IVP, intravenous pyelogram; RBC, red blood cell. related symptoms.
 CH AP TER 3
BLEEDING AND THROMBOSIS
Ba rb ara A. Ko n kle
T e human hemostatic system provi es a natural bal-
ance between procoagulant an anticoagulant orces. T e
procoagulant orces inclu e platelet a hesion an aggre-
gation an brin clot ormation; anticoagulant orces
inclu e the natural inhibitors o coagulation an brino-
lysis. Un er normal circumstances, hemostasis is regu-
late to promote bloo ow; however, it is also prepare
to clot bloo rapi ly to arrest bloo ow an prevent
exsanguination. A er blee ing is success ully halte ,
the system remo els the amage vessel to restore nor-
mal bloo ow. T e major components o the hemostatic
system, which unction in concert, are (1) platelets an
other orme elements o bloo , such as monocytes an
re cells; (2) plasma proteins (the coagulation an bri-
nolytic actors an inhibitors); an (3) the vessel wall.
STEP S O F NO RMAL HEMO STASIS
PLATELET PLUG FORMATION
On vascular injury, platelets a here to the site o injury,
usually the enu e vascular intimal sur ace. Platelet
a hesion is me iate primarily by Von Willebran ac-
tor (VWF), a large multimeric protein present in both
plasma an the extracellular matrix o the suben othe-
lial vessel wall, which serves as the primary “molecular
glue,” provi ing su cient strength to withstan the
high levels o shear stress that woul ten to etach
them with the ow o bloo . Platelet a hesion is also
acilitate by irect bin ing to suben othelial collagen
through speci c platelet membrane collagen receptors.
Platelet a hesion results in subsequent platelet acti-
vation an aggregation. T is process is enhance an
ampli e by humoral me iators in plasma (e.g., epi-
nephrine, thrombin); me iators release rom activate
platelets (e.g., a enosine iphosphate, serotonin); an
vessel wall extracellular matrix constituents that come
in contact with a herent platelets (e.g., collagen, VWF).
22
Activate platelets un ergo the release reaction, ur-
ing which they secrete contents that urther promote
aggregation an inhibit the naturally anticoagulant
en othelial cell actors. During platelet aggregation
(platelet-platelet interaction), a itional platelets are
recruite rom the circulation to the site o vascular
injury, lea ing to the ormation o an occlusive platelet
thrombus. T e platelet plug is anchore an stabilize
by the eveloping brin mesh.
T e platelet glycoprotein (Gp) IIb/IIIa (αIIbβ3) com-
plex is the most abun ant receptor on the platelet sur-
ace. Platelet activation converts the normally inactive
Gp IIb/IIIa receptor into an active receptor, enabling
bin ing to brinogen an VWF. Because the sur ace o
each platelet has about 50,000 Gp IIb/IIIa–bin ing sites,
numerous activate platelets recruite to the site o vas-
cular injury can rapi ly orm an occlusive aggregate by
means o a ense network o intercellular brinogen
bri ges. Because this receptor is the key me iator o
platelet aggregation, it has become an ef ective target or
antiplatelet therapy.
FIBRIN CLOT FORMATION
Plasma coagulation proteins (clotting factors) normally cir-
culate in plasma in their inactive orms. T e sequence
o coagulation protein reactions that culminate in the
ormation o brin was originally escribe as a water-
fall or a cascade. wo pathways o bloo coagulation
have been escribe in the past: the so-calle extrinsic,
or tissue actor, pathway an the so-calle intrinsic, or
contact activation, pathway. We now know that coagu-
lation is normally initiate through tissue actor ( F)
exposure an activation through the classic extrinsic
pathway but with critically important ampli cation
through elements o the classic intrinsic pathway, as illus-
trate in Fig. 3-1. T ese reactions take place on phos-
pholipi sur aces, usually the activate platelet sur ace.
Coagulation testing in the laboratory can re ect other
 23
Ve s s e l IX
injury
IX
T
F VIIIa
VIIa
IXa XIa
X

TFP I
X
XI

C
H
A
P
T
Va

E
Xa II

R
3
(Prothrombin)
Thrombin (IIa )

B
l
e
Fibrinoge n Fibrin

e
d
i
n
g
FIGURE 3 -1

a
n
Co a g u la t io n is in it ia te d b y t issu e a ct o r TF e xp o su re , Once the TF/FVIIa/FXa complex is ormed, tissue actor pathway

d
T
which, with actor (F) VIIa, activates FIX and FX, which in turn, with inhibitor (TFPI) inhibits the TF/FVIIa pathway, making coagulation

h
r
o
FVIII and FV as co actors, respectively, results in thrombin orma- dependent on the ampli cation loop through FIX/FVIII. Coagula-

m
b
tion and subsequent conversion o brinogen to brin. Throm- tion requires calcium (not shown) and takes place on phospholipid

o
s
i
s
bin activates FXI, FVIII, and FV, ampli ying the coagulation signal. sur aces, usually the activated platelet membrane.

in uences ue to the arti cial nature o the in vitro sys- A D E D

tems use (see below).
T e imme iate trigger or coagulation is vascular Thrombin Fibrin a s s e mbly
amage that exposes bloo to F that is constitutively
expresse on the sur aces o suben othelial cellular com-
D E D D E D D E D
ponents o the vessel wall, such as smooth muscle cells B
an broblasts. F is also present in circulating micropar- D E D D E D D E D
ticles, presumably she rom cells inclu ing monocytes
an platelets. F bin s the serine protease actor VIIa; the Fibrin
Fa ctor XIIIa cros s -linking
complex activates actor X to actor Xa. Alternatively, the
complex can in irectly activate actor X by initially con- D E D D E D D E D
verting actor IX to actor IXa, which then activates ac- C
tor X. T e participation o actor XI in hemostasis is not D E D D E D D E D
epen ent on its activation by actor XIIa but rather on
its positive ee back activation by thrombin. T us, ac-
P la s min Clot lys is
tor XIa unctions in the propagation an ampli cation,
rather than in the initiation, o the coagulation casca e.
Factor Xa can be orme through the actions o D D D E
either the F/ actor VIIa complex or actor IXa (with
actor VIIIa as a co actor) an converts prothrombin to FIGURE 3 -2
thrombin, the pivotal protease o the coagulation sys- Fib rin o rm a t io n a n d d isso lu t io n . A Fibrinogen is a trinodu-
tem. T e essential co actor or this reaction is actor Va. lar structure consisting o two D domains and one E domain.
Like the homologous actor VIIIa, actor Va is pro uce Thrombin activation results in an ordered lateral assembly o pro-
by thrombin-in uce limite proteolysis o actor V. to brils B with noncovalent associations. Factor XIIIa cross-links
T rombin is a multi unctional enzyme that converts the D domains on adjacent molecules C. Fibrin and brinogen
soluble plasma brinogen to an insoluble brin matrix. (not shown) lysis by plasmin occurs at discrete sites and results
Fibrin polymerization involves an or erly process o in intermediary brin(ogen) degradation products (not shown).
intermolecular associations (Fig. 3-2). T rombin also d-Dimers are the product o complete lysis o brin D, maintain-
activates actor XIII ( brin-stabilizing actor) to actor ing the cross-linked D domains.
24 XIIIa, which covalently cross-links an thereby stabi- XII
lizes the brin clot.
T e assembly o the clotting actors on activate cell TF
XI
membrane sur aces greatly accelerates their reaction VII VIIa XIIa
rates an also serves to localize bloo clotting to sites o IX
vascular injury. T e critical cell membrane components,
VIIa /TF XIa
aci ic phospholipi s, are not normally expose on rest- TFP I
ing cell membrane sur aces. However, when platelets,
monocytes, an en othelial cells are activate by vas- IXa
cular injury or in ammatory stimuli, the procoagulant
S
VIIIa
E
hea groups o the membrane anionic phospholipi s
C
T
I
become translocate to the sur aces o these cells or
O
N
release as part o microparticles, making them avail- X Xa AT
I
I
able to support an promote the plasma coagulation PC
Va
reactions. PS
C
a
r
PT Th
d
i
n
a
l
M
ANTITHRO MBOTIC MECHANISMS
a
n
Fibrinoge n Fibrin FDP
i
f
e
Several physiologic antithrombotic mechanisms act in
s
t
a
t
concert to prevent clotting un er normal circumstances.
i
P la s min
o
n
T ese mechanisms operate to preserve bloo ui -
s
o
PA
f
ity an to limit bloo clotting to speci c ocal sites o
H
P la s minoge n
e
vascular injury. En othelial cells have many antithrom-
m
a
botic ef ects. T ey pro uce prostacyclin, nitric oxi e,
t
o
l
FIGURE 3 -3
o
an ectoADPase/CD39, which act to inhibit platelet
g
i
Site s o a ct io n o th e o u r m a jo r p hysio lo g ic a n t it h ro m -
c
bin ing, secretion, an aggregation. En othelial cells
D
i
b o tic p a t h wa ys: antithrombin (AT); protein C/S (PC/PS); tissue
s
pro uce anticoagulant actors inclu ing heparan pro-
e
a
actor pathway inhibitor (TFPI); and the brinolytic system, con-
s
teoglycans, antithrombin, F pathway inhibitor, an
e
sisting o plasminogen, plasminogen activator (PA), and plasmin.
thrombomo ulin. T ey also activate brinolytic mecha- PT, prothrombin; Th, thrombin; FDP, brin(ogen) degradation
nisms through the pro uction o tissue plasminogen products. (Modi ed rom BAKonkle, AI Scha er, in DP Zipes et al [eds]:
activator 1, urokinase, plasminogen activator inhibitor, Braunwald’s Heart Disease, 7th ed. Philadelphia, Saunders, 2005.)
an annexin-2. T e sites o action o the major physi-
ologic antithrombotic pathways are shown in Fig. 3-3.
Antithrombin (or antithrombin III) is the major en othelial cells places it in proximity to the throm-
plasma protease inhibitor o thrombin an the other bin-thrombomo ulin complex, thereby enhancing
clotting actors in coagulation. Antithrombin neutral- its activation e ciency. Activate protein C acts as an
izes thrombin an other activate coagulation ac- anticoagulant by cleaving an inactivating activate ac-
tors by orming a complex between the active site o tors V an VIII. T is reaction is accelerate by a co ac-
the enzyme an the reactive center o antithrombin. tor, protein S, which, like protein C, is a glycoprotein
T e rate o ormation o these inactivating complexes that un ergoes vitamin K– epen ent posttranslational
increases by a actor o several thousan in the pres- mo i cation. Quantitative or qualitative e ciencies
ence o heparin. Antithrombin inactivation o thrombin o protein C or protein S, or resistance to the action
an other activate clotting actors occurs physiologi- o activate protein C by a speci c mutation at its tar-
cally on vascular sur aces, where glycosoaminoglycans, get cleavage site in actor Va ( actor V Lei en), lea to
inclu ing heparan sul ates, are present to catalyze these hypercoagulable states.
reactions. Inherite quantitative or qualitative e cien- issue actor pathway inhibitor ( FPI) is a plasma
cies o antithrombin lea to a li elong pre isposition to protease inhibitor that regulates the F-in uce extrin-
venous thromboembolism. sic pathway o coagulation. FPI inhibits the F/ actor
Protein C is a plasma glycoprotein that becomes an VIIa/ actor Xa complex, essentially turning of the
anticoagulant when it is activate by thrombin. T e F/ actor VIIa initiation o coagulation, which then
thrombin-in uce activation o protein C occurs physi- becomes epen ent on the “ampli cation loop”
ologically on thrombomo ulin, a transmembrane pro- via actor XI an actor VIII activation by throm-
teoglycan-bin ing site or thrombin on en othelial cell bin. FPI is boun to lipoprotein an can also be
sur aces. T e bin ing o protein C to its receptor on release by heparin rom en othelial cells, where it
is boun to glycosaminoglycans, an rom platelets.
T e heparin-me iate release o FPI may play a role
in the anticoagulant ef ects o un ractionate an low-
molecular-weight heparins.
THE FIBRINOLYTIC SYSTEM
Any thrombin that escapes the inhibitory ef ects o the
physiologic anticoagulant systems is available to con-
vert brinogen to brin. In response, the en ogenous
brinolytic system is then activate to ispose o intra-
vascular brin an thereby maintain or reestablish the
patency o the circulation. Just as thrombin is the key
protease enzyme o the coagulation system, plasmin is
the major protease enzyme o the brinolytic system,
acting to igest brin to brin egra ation pro ucts.
T e general scheme o brinolysis an its control is
shown in Fig. 3-4.
T e plasminogen activators, tissue type plasminogen
activator (tPA) an the urokinase-type plasminogen
activator (uPA), cleave the Arg560-Val561 bon o plas-
minogen to generate the active enzyme plasmin. T e
lysine-bin ing sites o plasmin (an plasminogen) per-
mit it to bin to brin, so that physiologic brinolysis is
“ brin speci c.” Both plasminogen (through its lysine-
bin ing sites) an tPA possess speci c a nity or brin
an thereby bin selectively to clots. T e assembly o
a ternary complex, consisting o brin, plasminogen,
an tPA, promotes the localize interaction between
plasminogen an tPA an greatly accelerates the rate o
plasminogen activation to plasmin. Moreover, partial
UPA P la s minoge n
tPA
PAI P la s min
Thrombin
α 2 P I-P la s min
FDP s
FIGURE 3 -4
A sch e m a t ic d ia g ra m o t h e f b rin o lyt ic syst e m . Tissue plas-
minogen activator (tPA) is released rom endothelial cells, binds
the brin clot, and activates plasminogen to plasmin. Excess brin
is degraded by plasmin to distinct degradation products (FDPs).
Any ree plasmin is complexed with α2-antiplasmin (α 2Pl). PAI,
plasminogen activator inhibitor; UPA, urokinase-type plasmino-
gen activator.
egra ation o brin by plasmin exposes new plasmin- 25
ogen an tPA-bin ing sites in carboxy-terminus lysine
resi ues o brin ragments to enhance these reactions
urther. T is creates a highly e cient mechanism to
generate plasmin ocally on the brin clot, which then
becomes plasmin’s substrate or igestion to brin eg-
ra ation pro ucts.
Plasmin cleaves brin at istinct sites o the brin
molecule, lea ing to the generation o characteris-
tic brin ragments uring the process o brinolysis
C
H
(Fig. 3-2). T e sites o plasmin cleavage o brin are
A
P
the same as those in brinogen. However, when plas-
T
E
R
min acts on covalently cross-linke brin, d- imers are
3
release ; hence, - imers can be measure in plasma
as a relatively speci c test o brin (rather than brino-
gen) egra ation. d-Dimer assays can be use as sen-
B
l
e
sitive markers o bloo clot ormation an have been
e
d
i
n
vali ate or clinical use to exclu e the iagnosis o
g
a
eep venous thrombosis (DV ) an pulmonary embo-
n
d
lism in selecte populations. In a ition, d- imer mea-
T
h
r
surement can be use to strati y patients, particularly
o
m
women, or risk o recurrent venous thromboembo-
b
o
s
lism (V E) when measure 1 month a er iscontinu-
i
s
ation o anticoagulation given or treatment o an initial
i iopathic event. d-Dimer levels may be elevate in the
absence o V E in el erly people.
Physiologic regulation o brinolysis occurs primarily
at three levels: (1) plasminogen activator inhibitors
(PAIs), speci cally PAI-1 an PAI-2, inhibit the physio-
logic plasminogen activators; (2) the thrombin-activatable
brinolysis inhibitor ( AFI) limits brinolysis; an
(3) α2-antiplasmin inhibits plasmin. PAI-1 is the pri-
mary inhibitor o tPA an uPA in plasma. AFI cleaves
the N-terminal lysine resi ues o brin, which ai in
localization o plasmin activity. α2-Antiplasmin is the
main inhibitor o plasmin in human plasma, inactivating
any non brin clot-associate plasmin.
APPROACHTOTHEPATIENT:
Bleeding and Thrombosis
CLINICALPRESENTATION Disor ers o hemostasis may be ei-
ther inherite or acquire . A etaile personal an amily
history is key in etermining the chronicity o symptoms
an the likelihoo o the isor er being inherite , as well
as provi ing clues to un erlying con itions that have con-
tribute to the blee ing or thrombotic state. In a ition,
the history can give clues as to the etiology by etermining
(1) the blee ing (mucosal an /or joint) or thrombosis (ar-
terial an /or venous) site an (2) whether an un erlying
blee ing or clotting ten ency was enhance by another
me ical con ition or the intro uction o me ications or
ietary supplements.
26
History of Bleeding A history o blee ing is the most Easy bruising an menorrhagia are common com-
important pre ictor o blee ing risk. In evaluating a plaints in patients with an without blee ing isor ers.
patient or a blee ing isor er, a history o at-risk situa- Easy bruising can also be a sign o me ical con itions in
tions, inclu ing the response to past surgeries, shoul be which there is no i enti able coagulopathy; instea , the
assesse . Does the patient have a history o spontaneous con itions are cause by an abnormality o bloo vessels
or trauma/surgery-in uce blee ing? Spontaneous hem- or their supporting tissues. In Ehlers-Danlos syn rome,
arthroses are a hallmark o mo erate an severe actor there may be posttraumatic blee ing an a history o joint
VIII an IX e ciency an , in rare circumstances, o other hyperextensibility. Cushing’s syn rome, chronic steroi
clotting actor e ciencies. Mucosal blee ing symptoms use, an aging result in changes in skin an subcutaneous
S
are more suggestive o un erlying platelet isor ers or Von tissue, an subcutaneous blee ing occurs in response to
E
C
Willebran isease (VWD), terme disorders of primary minor trauma. T e latter has been terme senile purpura.
T
I
O
hemostasis or platelet plug formation. Disor ers af ecting Epistaxis is a common symptom, particularly in chil-
N
I
primary hemostasis are shown in Table 3-1. ren an in ry climates, an may not re ect an un er-
I
A blee ing score has been vali ate as a tool to pre- lying blee ing isor er. However, it is the most common
ict patients more likely to have type 1 VWD (Interna- symptom in here itary hemorrhagic telangiectasia an
C
tional Society on T rombosis an Haemostasis Blee ing in boys with VWD. Clues that epistaxis is a symptom o
a
r
d
i
Assessment ool [www.isth.org/resource/resmgr/ssc/isth-ssc_ an un erlying blee ing isor er inclu e lack o seasonal
n
a
l
bleeding_assessment.pdf]). T is is most use ul tool in variation an blee ing that requires me ical evaluation
M
a
exclu ing the iagnosis o a blee ing isor er, an thus or treatment, inclu ing cauterization. Blee ing with erup-
n
i
f
e
avoi ing unnecessary testing. One stu y oun that a tion o primary teeth is seen in chil ren with more severe
s
t
a
low blee ing score (≤3) an a normal activate partial blee ing isor ers, such as mo erate an severe hemo-
t
i
o
n
thromboplastin time (aP ) ha 99.6% negative pre ic- philia. It is uncommon in chil ren with mil blee ing
s
o
tive value or the iagnosis o VWD. Blee ing symptoms isor ers. Patients with isor ers o primary hemosta-
f
H
e
that appear to be more common in patients with blee ing sis (platelet a hesion) may have increase blee ing a er
m
a
isor ers inclu e prolonge blee ing with surgery, ental ental cleanings an other proce ures that involve gum
t
o
l
proce ures an extractions, an /or trauma, menorrha- manipulation.
o
g
i
c
gia or postpartum hemorrhage, an large bruises (o en Menorrhagia is e ne quantitatively as a loss o >80 mL
D
i
escribe with lumps). o bloo per cycle, base on the quantity o bloo loss
s
e
a
s
require to pro uce iron- e ciency anemia. A complaint
e
o heavy menses is subjective an has a poor correla-
TABLE 3 -1 tion with excessive bloo loss. Pre ictors o menorrhagia
PRIMARY HEMOSTATIC (PLATELET PLUG) inclu e blee ing resulting in iron- e ciency anemia or
DISORDERS a nee or bloo trans usion, passage o clots >1 inch
Defects of Platelet Adhesion in iameter, an changing a pa or tampon more than
Von Willebrand disease
hourly. Menorrhagia is a common symptom in women
Bernard-Soulier syndrome (absence or dys unction o platelet with un erlying blee ing isor ers an is reporte in
Gp Ib-IX-V) the majority o women with VWD, women with actor
Defects of Platelet Aggregation XI e ciency, an symptomatic carriers o hemophilia.
Women with un erlying blee ing isor ers are more
Glanzmann’s thrombasthenia (absence or dys unction o
platelet glycoprotein [Gp] IIb/IIIa) likely to have other blee ing symptoms, inclu ing blee -
A brinogenemia ing a er ental extractions, postoperative blee ing, an
Defects of Platelet Secretion
postpartum blee ing, an are much more likely to have
menorrhagia beginning at menarche than women with
Decreased cyclooxygenase activity
menorrhagia ue to other causes.
Drug-induced (aspirin, nonsteroidal anti-in ammatory
agents, thienopyridines) Postpartum hemorrhage (PPH) is a common symptom
Inherited in women with un erlying blee ing isor ers. In women
Granule storage pool de ects with type 1 VWD an symptomatic carriers o hemophilia
Inherited A in whom levels o VWF an actor VIII usually normal-
Acquired ize uring pregnancy, PPH may be elaye . Women with a
Nonspeci c inherited secretory de ects
history o PPH have a high risk o recurrence with subse-
Nonspeci c drug ef ects
Uremia quent pregnancies. Rupture o ovarian cysts with intraab-
Platelet coating (e.g., paraprotein, penicillin) ominal hemorrhage has also been reporte in women
Defect of Platelet Coagulant Activity
with un erlying blee ing isor ers.
onsillectomy is a major hemostatic challenge, because
Scott’s syndrome
intact hemostatic mechanisms are essential to prevent
 TABLE 3 -2 27
excessive blee ing rom the tonsillar be . Blee ing may
HERBAL SUPPLEMENTS ASSOCIATED WITH
occur early a er surgery or a er approximately 7 ays
INCREASED BLEEDING
postoperatively, with loss o the eschar at the operative
Herbs with Potential Antiplatelet Activity
site. Similar elaye blee ing is seen a er colonic polyp
resection. Gastrointestinal (GI) blee ing an hematuria Ginkgo (Ginkgo biloba L.)
are usually ue to un erlying pathology, an proce ures Garlic (Allium sativum)
Bilberry (Vaccinium myrtillus)
to i enti y an treat the blee ing site shoul be un er- Ginger (Gingiber of cinale)
taken, even in patients with known blee ing isor ers. Dong quai (Angelica sinensis)
VWD, particularly types 2 an 3, has been associate with Fever ew (Tanacetum parthenium)

C
angio ysplasia o the bowel an GI blee ing. Asian ginseng (Panax ginseng)

H
A
Hemarthroses an spontaneous muscle hematomas American ginseng (Panax quinque olius)

P
T
Siberian ginseng/eleuthero (Eleutherococcus senticosus)

E
are characteristic o mo erate or severe congenital ac-

R
Turmeric (Circuma longa)
tor VIII or IX e ciency. T ey can also be seen in mo -

3
Meadowsweet (Filipendula ulmaria)
erate an severe e ciencies o brinogen, prothrombin, Willow (Salix spp.)
an actors V, VII, an X. Spontaneous hemarthroses
Coumarin-Containing Herbs

B
occur rarely in other blee ing isor ers except or severe

l
e
e
Motherwort (Leonurus cardiaca)

d
VWD, with associate actor VIII levels <5%. Muscle an

i
n
Chamomile (Matricaria recutita, Chamaemelum mobile)

g
so tissue blee s are also common in acquire actor VIII

a
Horse chestnut (Aesculus hippocastanum)

n
e ciency. Blee ing into a joint results in severe pain an

d
Red clover (Tri olium pratense)

T
h
swelling, as well as loss o unction, but is rarely associ- Fenugreek (Trigonella oenum-graecum)

r
o
m
ate with iscoloration rom bruising aroun the joint.

b
o
Li e-threatening sites o blee ing inclu e blee ing into the

oropharynx, where blee ing can obstruct the airway, into
the central nervous system, an into the retroperitoneum.
Central nervous system blee ing is the major cause o
blee ing-relate eaths in patients with severe congenital
actor e ciencies.
Prohemorrhagic Effects of Medications and Dietary Supplements
Aspirin an other nonsteroi al anti-in lammatory rugs
(NSAIDs) that inhibit cyclooxygenase 1 impair primary
hemostasis an may exacerbate blee ing rom another
cause or even unmask a previously occult mil blee ing
isor er such as VWD. All NSAIDs, however, can pre-
cipitate GI blee ing, which may be more severe in patients
with un erlying blee ing isor ers. he aspirin e ect on
platelet unction as assesse by aggregometry can persist
or up to 7 ays, although it has requently returne to
normal by 3 ays a ter the last ose. he e ect o other
NSAIDs is shorter, as the inhibitor e ect is reverse
when the rug is remove . hienopyri ines (clopi ogrel
an prasugrel) inhibit ADP-me iate platelet aggregation
an , like NSAIDs, can precipitate or exacerbate blee ing
symptoms.
Many herbal supplements can impair hemostatic unc-
tion (Table 3-2). Some are more convincingly associate
with a blee ing risk than others. Fish oil or concentrate
omega-3 atty aci supplements impair platelet unction.
T ey alter platelet biochemistry to pro uce more PGI3, a
more potent platelet inhibitor than prostacyclin (PGI2),
an more thromboxane A3, a less potent platelet activa-
tor than thromboxane A2. In act, iets naturally rich in
omega-3 atty aci s can result in a prolonge blee ing time
an abnormal platelet aggregation stu ies, but the actual
associate blee ing risk is unclear. Vitamin E appears to
s
i
s
inhibit protein kinase C–me iate platelet aggregation
an nitric oxi e pro uction. In patients with unexplaine
bruising or blee ing, it is pru ent to review any new me i-
cations or supplements an iscontinue those that may be
associate with blee ing.
Underlying Systemic Diseases That Cause or Exacerbate a Bleeding
Tendency Acquire blee ing isor ers are commonly sec-
on ary to, or associate with, systemic isease. he clini-
cal evaluation o a patient with a blee ing ten ency must
there ore inclu e a thorough assessment or evi ence o
un erlying isease. Bruising or mucosal blee ing may
be the presenting complaint in liver isease, severe renal
impairment, hypothyroi ism, paraproteinemias or amy-
loi osis, an con itions causing bone marrow ailure. All
coagulation actors are synthesize in the liver, an hepatic
ailure results in combine actor e iciencies. his is o ten
compoun e by thrombocytopenia rom splenomegaly
ue to portal hypertension. Coagulation actors II, VII, IX,
an X an proteins C, S, an Z are epen ent on vitamin
K or posttranslational mo i ication. Although vitamin
K is require in both procoagulant an anticoagulant
processes, the phenotype o vitamin K e iciency or the
war arin e ect on coagulation is blee ing.
T e normal bloo platelet count is 150,000–450,000/µL.
T rombocytopenia results rom ecrease pro uction,
increase estruction, an /or sequestration. Although
the blee ing risk varies somewhat by the reason or the
thrombocytopenia, blee ing rarely occurs in isolate
thrombocytopenia at counts <50,000/µL an usually not
until <10,000–20,000/µL. Coexisting coagulopathies, as
is seen in liver ailure or isseminate coagulation; in ec-
tion; platelet-inhibitory rugs; an un erlying me ical
28
con itions can all increase the risk o blee ing in the DV increases per eca e, with an approximate inci ence
thrombocytopenic patient. Most proce ures can be per- o 1/100,000 per year in early chil hoo to 1/200 per year
orme in patients with a platelet count o 50,000/µL. among octogenarians. Family history is help ul in eter-
T e level nee e or major surgery will epen on the mining i there is a genetic pre isposition an how strong
type o surgery an the patient’s un erlying me ical state, that pre isposition appears to be. A genetic thrombophilia
although a count o approximately 80,000/µL is likely that con ers a relatively small increase risk, such as being
su cient. a heterozygote or the prothrombin G20210A or actor V
Lei en mutation, may be a minor eterminant o risk in
HISTORYOF THROMBOSIS T e risk o thrombosis, like that o
an el erly in ivi ual un ergoing a high-risk surgical pro-
blee ing, is in uence by both genetic an environmental
S
ce ure. As illustrate in Fig. 3-5, a thrombotic event usu-
E
in uences. T e major risk actor or arterial thrombosis is
C
ally has more than one contributing actor. Pre isposing
T
I
atherosclerosis, whereas or venous thrombosis, the risk
O
actors must be care ully assesse to etermine the risk
N
actors are immobility, surgery, un erlying me ical con i-
I
o recurrent thrombosis an , with consi eration o the
I
tions such as malignancy, me ications such as hormonal
patient’s blee ing risk, etermine the length o anticoagu-
therapy, obesity, an genetic pre ispositions. Factors that
lation. Similar consi eration shoul be given in etermin-
increase risks or venous an or both venous an arterial
C
ing the nee , i any, to test the patient an amily members
a
r
thromboses are shown in Table 3-3.
d
i
or thrombophilias.
n
T e most important point in a history relate to venous
a
l
M
thrombosis is etermining whether the thrombotic event LABORATORYEVALUATION Care ul history taking an clinical
a
n
was i iopathic (meaning there was no clear precipitat- examination are essential components in the assessment
i
f
e
s
ing actor) or was a precipitate event. In patients with- o blee ing an thrombotic risk. he use o laboratory
t
a
t
i
out un erlying malignancy, having an i iopathic event is
o
n
s
the strongest pre ictor o recurrence o V E. In patients
o
f
who have a vague history o thrombosis, a history o
H
e
m
being treate with war arin suggests a past DV . Age is an
a
OCP us e
k
t
s
important risk actor or venous thrombosis—the risk o
o
i
Le g in ca s t
r
l
o
c
g
i
HRT us e
t
i
o
c
b
DVT
D
m
i
s
o
e
r
Thrombos is
h
a
T
s
e
TABLE 3 -3 S urge ry
RISK FACTORS FOR THROMBOSIS
VENOUS VENOUS AND ARTERIAL

Inherited Inherited
Factor V Leiden Homocystinuria
Prothrombin G20210A Dys brinogenemia
Antithrombin de ciency Mixed (inherited and
Protein C de ciency acquired) Le id e n
Fa c to r V
Protein S de ciency Hyperhomocysteinemia
Elevated actor VIII
Acquired
Acquired Malignancy Age
Age Antiphospholipid antibody
Previous thrombosis syndrome FIGURE 3 -5
Immobilization Hormonal therapy Th ro m b o t ic risk o ve r t im e . Shown schematically is an indi-
Major surgery Polycythemia vera vidual’s thrombotic risk over time. An underlying actor V Leiden
Pregnancy and puerperium Essential thrombocythemia mutation provides a “theoretically” constant increased risk. The
Hospitalization Paroxysmal nocturnal
Obesity thrombotic risk increases with age and, intermittently, with oral
hemoglobinuria
In ection contraceptive (OCP) or hormone replacement therapy (HRT) use;
Thrombotic thrombocytope-
APC resistance, nongenetic other events may increase the risk urther. At some point, the
nic purpura
Smoking Heparin-induced cumulative risk may increase to the threshold or thrombosis and
Unknown a thrombocytopenia result in deep venous thrombosis (DVT). Note: The magnitude
Elevated actor II, IX, XI Disseminated intravascular and duration o risk portrayed in the gure are meant or example
Elevated TAFI levels coagulation only and may not precisely re ect the relative risk determined
Low levels o TFPI by clinical study. (From BA Konkle, A Scha er, in DP Zipes et al [eds]:
a
Unknown whether risk is inherited or acquired.
Braunwald’s Heart Disease, 7th ed. Philadelphia, Saunders, 2005;
Abbrevia tions: APC, activated protein C; TAFI, thrombin-activatable modi ed with permission rom FR Rosendaal: Venous thrombosis:
brinolysis inhibitor; TFPI, tissue actor pathway inhibitor. Amulticausal disease. Lancet 353:1167, 1999.)
 aPTT 29
tests o coagulation complement, but cannot substitute or,
clinical assessment. No test exists that provi es a global
assessment o hemostasis. he blee ing time has been HMWK
PT
use to assess blee ing risk; however, it oes not pre ict
PK
blee ing risk with surgery an it is not recommen e or
this in ication. he PFA-100, an instrument that measures FXII FVII
platelet- epen ent coagulation un er low con itions, is
FXI
more sensitive an speci ic or VWD than the blee ing
time; however, it is not sensitive enough to rule out mil FIX

C
blee ing isor ers. PFA-100 closure times are prolonge in

H
A
patients with some, but not all, inherite platelet isor ers. FVIII

P
T
E
Also, its utility in pre icting blee ing risk has not been FX

R
etermine .

3
FV
For routine preoperative an preproce ure testing, an
abnormal prothrombin time (P ) may etect liver is- Prothrombin (FII)

B
ease or vitamin K e ciency that ha not been previously

l
e
e
Fibrinoge n (FI)

d
appreciate . Stu ies have not con rme the use ulness

i
n
g
o an aP in preoperative evaluations in patients with

a
n
a negative blee ing history. T e primary use o coagula-

d
T
h
tion testing shoul be to con rm the presence an type

r
o
m
o blee ing isor er in a patient with a suspicious clinical FIGURE 3 -6

b
o
history. Co a g u la t io n a ct o r a ct ivit y tested in the activated partial

Because o the nature o coagulation assays, proper
sample acquisition an han ling is critical to obtaining
vali results. In patients with abnormal coagulation assays
who have no blee ing history, repeat stu ies with atten-
tion to these actors requently results in normal values.
Most coagulation assays are per orme in so ium citrate
anticoagulate plasma that is recalci e or the assay.
Because the anticoagulant is in liqui solution an nee s
to be a e to bloo in proportion to the plasma volume,
incorrectly lle or ina equately mixe bloo collection
tubes will give erroneous results. Vacutainer tubes shoul
be lle to >90% o the recommen e ll, which is usu-
ally enote by a line on the tube. An elevate hemato-
crit (>55%) can result in a alse value ue to a ecrease
plasma-to-anticoagulant ratio.
Screening Assays he most commonly use screening tests
are the P , aP , an platelet count. he P assesses the
actors I ( ibrinogen), II (prothrombin), V, VII, an X
(Fig. 3-6). he P measures the time or clot ormation o the
citrate plasma a ter recalci ication an a ition o throm-
boplastin, a mixture o F an phospholipi s. he sensi-
tivity o the assay varies by the source o thromboplastin.
he relationship between e ects in secon ary hemostasis
( ibrin ormation) an coagulation test abnormalities is
shown in Table 3-4. o a just or this variability, the over-
all sensitivity o i erent thromboplastins to re uction
o the vitamin K– epen ent clotting actors II, VII, IX,
an X in anticoagulation patients is now expresse as the
International Sensitivity In ex (ISI). An inverse relation-
ship exists between ISI an thromboplastin sensitivity. he
international normalize ratio (INR) is then etermine
base on the ormula: INR = (P patient/P normal mean)ISI.
s
i
s
thromboplastin time (aPTT) in red and prothrombin time (PT) in
green, or both. F, actor; HMWK, high-molecular-weight kinino-
gen; PK, prekallikrein.
T e INR was evelope to assess stable anticoagulation
ue to re uction o vitamin K– epen ent coagulation ac-
tors; it is commonly use in the evaluation o patients with
liver isease. Although it oes allow comparison between
laboratories, reagent sensitivity as use to etermine the
ISI is not the same in liver isease as with war arin anti-
coagulation. In a ition, progressive liver ailure is asso-
ciate with variable changes in coagulation actors; the
egree o prolongation o either the P or the INR only
roughly pre icts the blee ing risk. T rombin generation
has been shown to be normal in many patients with mil
to mo erate liver ys unction. Because the P only mea-
sures one aspect o hemostasis af ecte by liver ys unc-
tion, we likely overestimate the blee ing risk o a mil ly
elevate INR in this setting.
T e aP assesses the intrinsic an common coagula-
tion pathways; actors XI, IX, VIII, X, V, an II; brino-
gen; prekallikrein; high-molecular-weight kininogen; an
actor XII (Fig. 3-6). T e aP reagent contains phospho-
lipi s erive rom either animal or vegetable sources that
unction as a platelet substitute in the coagulation path-
ways an inclu es an activator o the intrinsic coagulation
system, such as nonparticulate ellagic aci or the particu-
late activators kaolin, celite, or micronize silica.
T e phospholipi composition o aP reagents varies,
which in uences the sensitivity o in ivi ual reagents to
clotting actor e ciencies an to inhibitors such as hepa-
rin an lupus anticoagulants. T us, aP results will vary
30 TABLE 3 -4
plasma an patient plasma are mixe in a 1:1 ratio, an the
HEMOSTATIC DISORDERS AND COAGULATION TEST
aP or P is etermine imme iately an a er incuba-
ABNORMALITIES
tion at 37°C or varying times, typically 30, 60, an /or 120
Pro lo n g e d Activate d Pa rtia l Th ro m b o p la stin Tim e a PTT
min. With isolate actor e ciencies, the aP will cor-
No clinical bleeding—↓ actor XII, high-molecular-weight rect with mixing an stay correcte with incubation. With
kininogen, prekallikrein aP prolongation ue to a lupus anticoagulant, the mix-
Variable, but usually mild, bleeding—↓ actor XI, mild ↓ actor
ing an incubation will show no correction. In acquire
VIII and actor IX
Frequent, severe bleeding—severe de ciencies o actors VIII neutralizing actor antibo ies, notably an acquire actor
and IX VIII inhibitor, the initial assay may or may not correct
S
Heparin and direct thrombin inhibitors imme iately a er mixing but will prolong or remain
E
C
prolonge with incubation at 37°C. Failure to correct with
T
Pro lo n g e d Pro t h ro m b in Tim e PT
I
O
mixing can also be ue to the presence o other inhibitors
N
Factor VII de ciency
I
or inter ering substances such as heparin, brin split pro -
I
Vitamin K de ciency—early
War arin anticoagulation ucts, an paraproteins.
Direct Xa inhibitors (rivaroxaban, apixaban)
Specific Factor Assays Decisions to procee with speci c
C
a
Pro lo n g e d a PTT a n d PT
r
clotting actor assays will be in uence by the clinical
d
i
n
Factor II, V, X, or brinogen de ciency
a
situation an the results o coagulation screening tests.
l
M
Vitamin K de ciency—late
Precise iagnosis an ef ective management o inherite
a
n
Direct thrombin inhibitors
i
an acquire coagulation e ciencies necessitate quan-
f
e
s
Pro lo n g e d Th ro m b in Tim e
t
titation o the relevant actors. When blee ing is severe,
a
t
i
Heparin or heparin-like inhibitors
o
speci c assays are urgently require to gui e appropriate
n
s
Direct thrombin inhibitors (e.g., dabigatran, argatroban, therapy. In ivi ual actor assays are usually per orme
o
f
bivalirudin)
H
as mo i cations o the mixing stu y, where the patient’s
e
Mild or no bleeding—dys brinogenemia
m
plasma is mixe with plasma e cient in the actor being
a
Frequent, severe bleeding—a brinogenemia
t
o
stu ie . T is will correct all actor e ciencies to >50%,
l
o
Pro lo n g e d PT a n d /o r a PTT No t Co rre cte d wit h Mixin g
g
thus making prolongation o clot ormation ue to a ac-
i
c
wit h No rm a l Pla sm a
D
tor e ciency epen ent on the actor missing rom the
i
s
Bleeding—speci c actor inhibitor
e
a e plasma.
a
s
No symptoms, or clotting and/or pregnancy loss—lupus
e
anticoagulant Testing for Antiphospholipid Antibodies Antibo ies to phos-
Disseminated intravascular coagulation
Heparin or direct thrombin inhibitor
pholipi s (car iolipin) or phospholipi -bin ing proteins
(β2-microglobulin an others) are etecte by enzyme-
Ab n o rm a l Clo t So lu b ilit y
linke immunosorbent assay (ELISA). When these anti-
Factor XIII de ciency bo ies inter ere with phospholipi - epen ent coagulation
Inhibitors or de ective cross-linking
tests, they are terme lupus anticoagulants. T e aP has
Ra p id Clo t Lysis variability sensitivity to lupus anticoagulants, epen ing in
De ciency o α2-antiplasmin or plasminogen activator inhibitor 1 part on the aP reagents use . An assay using a sensitive
Treatment with brinolytic therapy reagent has been terme an LA-PTT. T e ilute Russell
viper venom test ( RVV ) an the tissue thromboplastin
inhibition ( I) test are mo i cations o stan ar tests
rom one laboratory to another, an the normal range in with the phospholipi reagent ecrease , thus increasing
the laboratory where the testing occurs shoul be use in the sensitivity to antibo ies that inter ere with the phos-
the interpretation. Local laboratories can relate their aP pholipi component. T e tests, however, are not speci c or
values to the therapeutic heparin anticoagulation by cor- lupus anticoagulants, because actor e ciencies or other
relating aP values with irect measurements o heparin inhibitors will also result in prolongation. Documentation
activity (anti-Xa or protamine titration assays) in samples o a lupus anticoagulant requires not only prolongation o
rom heparinize patients, although correlation between a phospholipi - epen ent coagulation test but also lack o
these assays is o en poor. T e aP reagent will vary in correction when mixe with normal plasma an correc-
sensitivity to in ivi ual actor e ciencies an usually tion with the a ition o activate platelet membranes or
becomes prolonge with in ivi ual actor e ciencies o certain phospholipi s (e.g., hexagonal phase).
30–50%.
Other Coagulation Tests T e thrombin time anthe rep-
Mixing Studies Mixing stu ies are use to evaluate a pro- tilase time measure brinogen conversion to brin an
longe aP or, less commonly P , to istinguish between are prolonge when the brinogen level is low (usually
a actor e ciency an an inhibitor. In this assay, normal <80–100 mg/ L) or qualitatively abnormal, as seen in

inherite or acquire ys brinogenemias, or when brin/
brinogen egra ation pro ucts inter ere. T e thrombin
time, but not the reptilase time, is prolonge in the pres-
ence o heparin. T e thrombin time is marke ly prolonge
in the presence o the irect thrombin inhibitor, abi-
gatran; a ilute thrombin time can be use to assess rug
activity. Measurement o anti– actor Xa plasma inhibitory
activity is a test requently use to assess low-molecular-
weight heparin (LMWH) levels, as a irect measurement o
31
an testing can be per orme at least 3 weeks later. As a
sensitive marker o coagulation activation, the quantitative
d- imer assay, rawn 4 weeks a er stopping anticoagula-
tion, can be use to strati y risk o recurrent thrombosis in
patients who have an i iopathic event.
Measures of Platelet Function T e blee ing time has been
use to assess blee ing risk; however, it has not been oun
to pre ict blee ing risk with surgery, an it is not recom-

C
un ractionate heparin (UFH) activity, or to assess activity men e or use or this in ication. T e PFA-100 an simi-

H
A
o the new irect Xa inhibitors rivaroxaban or apixaban. lar instruments that measure platelet- epen ent coagula-

P
T
tion un er ow con itions are generally more sensitive an

E
Drug in the patient sample inhibits the enzymatic conver-

R
sion o an Xa-speci c chromogenic substrate to colore speci c or platelet isor ers an VWD than the blee ing

3
pro uct by actor Xa. Stan ar curves are create using time; however, ata are insu cient to support their use to
multiple concentrations o rug an are use to calculate pre ict blee ing risk or monitor response to therapy, an

B
the concentration o anti-Xa activity in the patient plasma. they will be normal in some patients with platelet isor ers

l
e
e
or mil VWD. When they are use in the evaluation o a

d
i
n
Laboratory Testing for Thrombophilia Laboratory assays to patient with blee ing symptoms, abnormal results, as with

g
a
etect thrombophilic states inclu e molecular iagnostics

n
the blee ing time, require speci c testing, such as VWF

d
T
an immunologic an unctional assays. T ese assays vary assays an /or platelet aggregation stu ies. Because all o

h
r
o
in their sensitivity an speci city or the con ition being these “screening” assays may miss patients with mil blee -

m
b
teste . Furthermore, acute thrombosis, acute illnesses, ing isor ers, urther stu ies are nee e to e ne their role

o
s
i
in ammatory con itions, pregnancy, an me ications

s
in hemostasis testing.
af ect levels o many coagulation actors an their inhibi- For classic platelet aggregometry, various agonists
tors. Antithrombin is ecrease by heparin an in the are a e to the patient’s platelet-rich plasma an plate-
setting o acute thrombosis. Protein C an S levels may let aggregation is measure . ests o platelet secretion in
be increase in the setting o acute thrombosis an are response to agonists can also be measure . T ese tests are
ecrease by war arin. Antiphospholipi antibo ies are af ecte by many actors, inclu ing numerous me ica-
requently transiently positive in acute illness. esting or tions, an the association between minor e ects in aggre-
genetic thrombophilias shoul , in general, only be per orme gation or secretion in these assays an blee ing risk is not
when there is a strong amily history o thrombosis an clearly establishe .
results woul af ect clinical ecision making.
Because thrombophilia evaluations are usually per-
orme to assess the nee to exten anticoagulation, test-
Ac kn o w l ed g men t
ing shoul be per orme in a stea y state, remote rom the
Robert I. Handin, MD, contributed this chapter in the
acute event. In most instances, war arin anticoagulation
16th edition, and some material from that chapter has
can be stoppe a er the initial 3–6 months o treatment,
been retained here.
Another random document with
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 Plate VIII
The fringe of the robe from the Tomb of Charlemagne. To face p. 291.
Plate VII shows one medallion of a piece of silk found on the body
of Charlemagne when the grave was opened in the time of the
present German Emperor. It is certainly not of Charlemagne’s time.
But it seems a fairly safe guess to suppose that his well-known
regard for his favourite beast Abulabaz, who died only four years
before him, caused his son to have the body wrapped in one of the
robes decorated with elephants which we know that he possessed;
and that either in the year 1000, when Otho III opened the tomb, or
in 1166, under Barbarossa, when Charlemagne was canonized, this
piece of silk replaced the decayed robe originally buried there. We
know of the two elephant-robes referred to from Anastasius[270], who
gives an enormous list of the art works in gold and silver and silk and
cloth of gold which were wrought for Leo III, Charlemagne’s
contemporary. One item is “two robes of Syrian purple, with borders
of cloth of gold wrought with elephants”. These robes Leo gave to
Charlemagne.
We can all but give the exact date of this remarkable Byzantine
beast. The inscription breaks off exactly where the date came. The
Greek inscription worked in the stuff (Plate VIII) sets forth that it was
made “under Michael the great chamberlain and controller of the
privy purse of the emperor, when Peter was the manager of
Zeuxippos”, i. e. the Byzantine court factory in Negropont. Then
comes the tantalizing Indictionos (? B), and the date is lost.
Dreger, in his Europäische Weberei und Stickerei,[271] gives some
early examples of elephants in art. His Figure 37b shows an archaic
silver relief of an elephant with a castle containing armed men. His
Figure 37a shows a silk stuff of the seventh or eighth century, of
Asiatic manufacture, with circular medallions containing elephants,
griffins and winged horses, hippogryffs; and he remarks that “the
elephant is one of the most holy beasts of Buddhism”. This silk stuff
is shown in our Plate IX from a photograph of the original. A
comparison of these elephants with the elephant shown in Plate VIII
makes it fairly clear that the Charlemagne stuff is later than the other,
while in all of the details of the beast itself, ears, three toes, eye,
trunk, they are exactly the same. Each has a tree behind the
elephant; but while the Charlemagne tree is a piece of stiff
conventional work, the other is a natural tree with leaves and fruit,
much resembling the vegetable ornamentation of some early
Egyptian stuffs. Another feature pointing in the same direction is the
thirty-two conventional patterns on the circular enclosing border.
These in the earlier piece are twenty-eight plain disks.
There is an example of sculptured elephants something like this
one, but much more like the real beast, especially about the feet.
The elephants are the legs of the ivory chair[272] of Urso, at
Canossa; he was Bishop of Bari and Canossa 1078-89.
Something should be said about the language spoken by the
people of France and Germany in the times with which we are
dealing, the reference to a rustic tongue being not infrequent.
In the Council convened by Charlemagne at Tours in the year 813,
equally representing Eastern France and Western France, Austrasia
and Neustria, Germany and the Galliae, the bishops in the
Transalpine Empire were enjoined to be diligent in preaching, and to
take care that their discourses should be rendered either into
Romana Rustica or into Theotisc or Deutsch, that all might
understand. It may be of interest to give the earliest specimens we
have of these native languages. Philologically, these examples are of
the very highest importance.

Plate IX
Silk stuff of the seventh or eighth century. To face p. 292.
 In 841, after the dreadful battle of Fontenai near Vézelay in
Burgundy, where Charles-le-Chauve and Louis-le-Germanique
combined against their brother Lothar and their nephew Pepin and
defeated them, they held a Congress at Strassburg to confirm their
alliance.
Louis and Charles each made announcement in Latin of the
purpose of their agreement, and of their intention to take in public an
oath each to other. That done, Louis, as the elder, first took the oath.
Being the ruler of the German portion of the empire, he took the oath
in the language of the Franks, the Romance tongue, Rustica
Romana, in order that the adherents of Charles might hear and
understand his undertaking. These were the words of his oath,
probably read by a chancellor, for the Latin account[273] says haec
se servaturum testatus est:—
“Pro Deo amur et pro christian poblo et nostro commun salvament,
dist di[274] in avant, in quant Deus savir et podir me dunat[275], si
salvarai eo cist meon fradre Karlo, et in aiudha et in cadhuna[276]
cosa, si cum om[277] per dreit[278] son fradra salvar dist, in o quid il
mi altresi fazet[279]; et ab Ludher nul plaid numquam prindrai, qui
meon vol[280] cist meon fradre Karle in damno sit.”
Then Charles said the same in the language of the Germans, the
Teudisc or Deutsch tongue. The Latin account uses a different
phrase here, haec eadem verba testatus est.
“In Godes minna ind in thes christianes folches ind unser bedhero
gehaltnissi, fon thesemo dage frammordes, so fram so mir Got
geuuizci indi mahd furgibit, so haldi thesan minan bruodher, soso
man mit rehtu sinan bruodher scal, in thiu, thaz er mig so sama duo;
indi mit Ludheren in nohheiniu thing ne gegango, the minan uuillon
imo ce scadhen uuerdhen.”
The peoples then swore an oath, each in their own, not the
other’s, tongue. The Frank people swore in the Romance language:
—
 “Si Lodhuvigs sagrament, que son fradre Karlo iurat, conservat, et
Karlus meos sendra de suo part non los tanit, si io returnar non l’int
pois: ne io ne neuls, cui eo returnar int pois, in nulla aiudha contra
Lodhuuuig nun li iv er.”
The others then swore in the Teudisc language:—
“Oba Karl then eid, then er sinemo bruodher Ludhuuuige gesuor,
geleistit, indi Ludhuuuige min herro then er imo gesuor forbrihchit, ob
ih inan es iruuenden ne mag: noh ih no thero nohhein, then ih es
iruuenden mag, uuidhar Karle imo ce follusti ne uuirdhit.”

Plate X
The abrenuntiatio diaboli of Archbishop Boniface. To face p. 295.
An example of language nearly a hundred years earlier than this is
found in the renunciation of the devil and the declaration of belief in
God which our own Boniface required of his converts from
paganism. The form is found attached to the decrees of a
Council[281] held by Boniface, probably in the year 743. It exists in a
Vatican manuscript (Vat. Palat, nro. 577, fol. 6, 7), which Pertz and
other scholars believe to be of contemporary date. The form is of
such extreme interest that I have had that part of it which is at the
foot of folio 6 photographed, by the kind help of a friend in the
Vatican Library; see figure 10, the four lowest lines.
This is the form:—
“Forsachistu diobolae? Ec forsacho diabolae.
End allum diobolgelde? End ec forsacho allum diobolgeldae.
End allum dioboles uuercum? End ec forsacho allum dioboles
uuercum and uuordum thunaer ende uuoden ende saxnote ende
allum them unholdum the hira genotas sint.
Gelobistu in Got alamehtigen fadaer? Ec gelobo in Got
alamechtigen fadaer.
Gelobistu in Crist Godes suno? Ec gelobo in Crist Godes suno.
Gelobistu in halogen Gast? Ec gelobo in halogen Gast.”
An isolated piece of early “Saxon” is found in one of the letters
contained in vol. iii of the Epistolae of the Monumenta Germaniae
Historica, the volume containing Epistolae Meròwingici et Karolini
Aevi (Berlin, 1892). The letter is No. 146 of the “letters of Boniface
and Lull”. It is written by a poor and humble monk to a personage
described as reverentissimus atque sanctissimus, who would appear
to have had the reputation of not carrying out his purposes. The
proverb looks like the eighth century; Brandl thinks that it is pre-
Christian. The dialect is probably Northumbrian, varied by a West-
Saxon or a German scribe.
“I hear of thee that thou proposest to make a journey: I exhort thee
not to fail. Do what thou hast begun. Remember the Saxon saying

Oft daedlata dôme foreldit

Sigisitha gahuem suuyltit thi âna”.

That is, Often the tardy man (deed-late) loses glory, some victory;
thus he dies solitary.
 The suggested date of the letter is a.d. 757-786.
Mention was made on page 57 of the inscriptions which exist on
the great shaft of a cross in the churchyard of Bewcastle in
Cumberland. These inscriptions are the earliest extant pieces of
English prose. They give the names of the King of Mercia, Wulfhere,
his queen and her sister, with the date “first year of Ecgfrith King of
this realm”, that is, a.d. 670. We have another inscription dated in
Ecgfrith’s reign, that, namely, on the dedication stone of the basilica
of St. Paul at Jarrow, “in the 15th year of King Ecgfrith and the fourth
year of Abbat Ceolfrid”, so that the manner of dating the Bewcastle
cross was that usual at the time; the Jarrow inscription is in
Latin[282]. Plate XI shows a facsimile of all except the two top lines
(which were beyond my reach) of the main inscription on the
Bewcastle cross, a copy of which is given in a note on page 57. The
runes on Plate XI begin with the gar of Wothgar, the second of the
three persons who “set up this slender token of victory in memory of
Alchfrith once King and son of Oswy”, the half-brother of King
Ecgfrith; mention has been made of him on page 9.
 Plate XI
Runes incised on the Bewcastle Cross. To face p. 296.
 Plate XII
Runes incised on the Ruthwell Cross.
To face p. 297.
The earliest pieces of English verse in existence in their original
form are found on the Cross at Ruthwell in Dumfriesshire, a
monument of equal magnificence with the Bewcastle Cross, and
probably about fourteen years later. King Ecgfrith was slain by the
Picts in 685, and the Angles were never dominant in the south-west
of Scotland after his death. Plate XII shows a portion of the many
runes on this great monument, which is described at pages 235-254
of my little book on Theodore and Wilfrith. Reading across the top
and down the right side the runes are as follows:—
Krist wæs on rodi hwethræ ther fusæ fearran kwomu æththilæ til
anum ic thæt al bih[eald]. Christ was on the cross, and there
hastening from far came they to the noble prince. I that all beh[eld].
Beginning at the top again and reading down the left side, we
have:—
Mith strelum giwundad alegdun hiæ hinæ limwoerignæ gistoddun
him (æt his licæs heafdum). With missiles wounded, they laid Him
down limb-weary, they stood at His body’s head.
 CHAPTER XVIII
Alcuin’s latest days.—His letters mention his ill health.—His appeals for the
prayers of friends, and of strangers.—An affectionate letter to Charlemagne.—The
death scene.

Alcuin’s health began to break in the later part of Ep. 147. June 26,
the year 800, or early in 801. In June, 800, he 800.
wrote a letter to Arno of Salzburg which shows that
he had in the first days of the month travelled with Karl from Tours to
Aix by way of Orleans and Paris, and after a debate with Felix the
Adoptionist had returned to Tours. We do not find in this long letter
any mention of failing health. Indeed, he overflows with
affectionateness, a feeling always displayed in his letters to Arno. “I
am sending to your dearness three little gifts; a tent to protect your
venerated head from the rain[283], a bed-cover to keep warm your
sacred breast, and a glass in which your bread may be dipped at
table, that whenever they are used they may bring to your sanctity a
recollection of my name.”
In this letter he describes his debate with Felix.
“I have had a great dispute with the heretic Felix in presence of the
lord king and holy fathers. He was obdurate; would recognize the
authority of no one who took an opposite view; held himself to be
wiser than all in this, that he was more foolish than all. But the divine
clemency touched his heart; he confessed that he had of late been
carried away by a false opinion; he professed that he held firmly the
Catholic faith. We could not see into his mind, and we left the cause
to the Judge of secret things. We handed him over to Laidrad [the
Bishop of Lyon (798-814)] our dearest son, who is to keep him and
see whether it is true that he believes, and whether he will write
letters condemning the heresy which he has preached. The king had
intended to send him to Archbishop Riculf [of Maintz] to be kept and
chastised; and his presbyter, who is worse than his master, was to
be sent to you and your providence. But now that they say they are
converted to the Catholic faith, they have been handed over to
Laidrad, who is to test their sincerity.”
On May 24, 801, Alcuin received a letter from Ep. 189. May,
Arno, Archbishop of Salzburg, at nine o’clock in the 802.
morning, and the messenger told him he must
leave again at three in the afternoon. In the course of the six hours
he dictated fourteen paragraphs in reply. One of these concerned his
health. “My Candidus has been able to tell you all about my
weakness. It is therefore superfluous to write on the subject, except
to say that all bodily fitness has left me, and pleasures of the world
have fled far away.”
The interesting remark in this letter that the messenger from
Salzburg to Tours, a distance of some six hundred miles, must go
back in six hours is not the only interesting detail. We learn, also,
that many letters were lost in the difficulties of the journey. The eyes
of the Sassenach of to-day, who rides some forty miles in a Scottish
mail-cart in Sutherland, and sees the letters shied out into kailyards
and steadings, are opened to the possibilities of loss in primitive
methods of letter-carrying. The admirable arrangements of the early
Roman empire, for conveyance of men and things, had been thrown
into chaos long before Alcuin’s time, and special messengers, or
“runners”, were used by important people for the transmission of
letters.
“To Arno. My devotedness is greatly grieved by Ep. 189. May,
the unfaithfulness of those whom I have trusted 802.
with letters to you. Last year I sent to you on your
return from Italy two letters, and I also sent to you other two to meet
you on your arrival at the palace [Aachen]. I do not know that any of
them reached your presence.”
Alcuin wrote to the Emperor Charles in 802, or Ep. 193.
possibly in 803, begging that he might be allowed
to stay quietly at St. Martin’s, Tours. “I am so very weak in body that I
am unequal to any more travelling or labour. To speak truth, all the
fitness and strength of my body has left me; it has gone, and day by
day will be further away; I fear it will never come back to me in this
world.”
Again, writing to Arno in 802 or 803, he tells him Ep. 194.
how he longs to see him at St. Martin’s, “not for the
sake of your black hair, but for your most sweet eyes and lovable
talk.” Though bidden to the palace, where he would have met him,
his poor little body was too weak for the journey: he could not go.
In another letter to Arno he writes: “I have been Ep. 196. a.d. 802-
summoned to my lord David [Charlemagne], but 3.
my bodily weakness prevented my going: the will of Ep. 198. a.d. 802-
God detained me.” We have his letter of excuse to 3.
the emperor. He begins with the simile of the aged
soldier, unable not only to bear the weight of armour, but even to
support his own body. Then he proceeds: “To speak simply, let not
the mind of my lord be inflamed against me for my delay; I am not
strong enough to come. A more favourable opportunity may occur.”
He became more than ever pressing in his Ep. 230.
entreaties that his friends would pray for him. In
seeking for the prayers of others we find him turning to a part of
England of which we do not appear to have any other mention in his
letters, namely, Norfolk and Suffolk, called then the dioceses of
Elmham and Dunwich (see page 159). In like manner, and for a like
purpose, he wrote to the brethren of Candida Casa, i. e. Whithorn in
Galloway, the following letter:—
“I pray the unanimity of your piety to have my Ep. 271. a.d. 804.
name in memory. Deign to intercede for my
littleness in the church of your most holy father Nynia the bishop.
“He shone bright with many virtues, as has recently been related
to me by a skilful poem which our faithful disciples the scholars of
the church of York have sent. In that poem I have discerned in that
which I have read there both the skill of the writer and the holiness of
him who wrought the miracles. Wherefore, I pray you, by your holy
intercessions to commend me to his prayers, that by the most holy
prayers of the same your father, and by the assiduous intercessions
of your love, I may receive pardon for my sins, by the mercy of the
God Christ, and may come to the communion of saints who have
bravely conquered the labours of the world, and have received the
crown of perpetual praise.
“I send to the body of our holy father Nyniga (sic) a robe of whole
silk, that my name may be remembered, and that I may merit to have
always the pious intercession both of him and of you.
“May Christ’s right hand protect and rule you, brothers.”
Here is a very touching letter, which sets clearly before our eyes
the dear affectionate old man—old as men then counted age—
beaten at last by bodily weakness, while his heart was as loving as
ever. It is addressed to “the most longed for lord David, most worthy
of all honour.”
“Day by day, with hungry intentness of heart, my Ep. 170. a.d. 801,
ears hanging on the words of messengers, I early autumn.
wondered anxiously what they could tell me of my
most sweet lord David: when he would come home; when he would
return to his own land. At last, though late, the wished-for voice
sounded in the ears of my desire: ‘He will soon come. He has
already crossed the Alps, he whose presence thou hast desired, O
Albinus, with such fervour of mind.’ And then I cried over and over
again with tearful voice: ‘O Lord Jesu, why dost thou not give me the
wings of an eagle? Why dost thou not grant me the translation of the
prophet Abacuc[284] for one day, or even one hour, that I might
embrace and kiss the steps of him my dearest one, and—above all
that can be loved in this world—see the most clear eyes of my
sweetest one, and hear his most joyous words. And why dost thou,
mine enemy of fever, oppress me at this inopportune time, and not
permit me to have my wonted alacrity of body, so that, though tardily,
that might be accomplished which promptly it cannot do.’”
The dates and the story of his final illness and his death are found,
as we have seen (Ch. II), in the life written about twenty years later
by a pupil of Alcuin’s favourite priest Sigulf, and more concisely in
the Annals of Pettau, a monastery not far from Salzburg, and
therefore likely to be well-informed. Some of the touching facts
should be repeated here.
 Early in 804 he was evidently failing. He prayed earnestly that he
might die on the day on which the Holy Spirit came upon the
Apostles in tongues of fire. All through Lent he was able to move
about, night after night, to the several basilicas of saints which were
included in the monastery of St. Martin, cleansing himself from his
sins with much groaning. He kept the solemnity of the Lord’s
Resurrection; but on the night of the Ascension he fell upon his
couch, oppressed by languor even unto death, and unable to speak.
The Annals of Pettau tell us that this was a paralytic stroke, and that
it fell on Thursday, May 8, in the evening, after sunset. On the third
day before his death he recovered the power of speech, and with a
voice of exultation sang through his favourite antiphon, O clavis
David, based upon Isaiah xxii. 22: “The key of the house of David I
will lay upon his shoulder; so he shall open and none shall shut, he
shall shut and none shall open.” Then he repeated a number of
verses from several psalms: “Like as the hart desireth the
waterbrooks.” “O how amiable are Thy dwellings, Thou Lord of
hosts; blessed are they that dwell in Thy house.” “Unto Thee do I lift
up mine eyes.” “One thing I have desired of the Lord.” “Unto Thee, O
Lord, will I lift up my soul.” And others of like kind. On the day of
Pentecost, matins having been said, at full dawn, just at the hour at
which he was wont to enter the church for Mass, the holy soul of
Alcuin was released from the flesh. He had prayed months before
that he might die on Whit Sunday; on Whit Sunday he died.
 APPENDIX A
(Page 26)

It would appear that when Alcuin was not allowed by Charlemagne

to retire to Fulda, as he had wished to do, an impulse of affectionate
responsibility brought him to pour himself out in advice and help to
those with whom he had hoped to spend his last days. This is his
letter to the monks of Fulda.
“To the most holy, and by us with all love to be Ep. 186. a.d. 801-
cherished, the brethren of the holy Boniface[285], 2.
our father and protector, the humble levite Alchuin
wishes eternal beatitude in Christ.
“I am mindful of your most sweet love, with which you most
benignantly received me long ago with all joy. Greatly as I then was
glad in your presence, so greatly is my mind now tortured in your
absence, desiring to see you whom it loves, to have present you
whom it esteems. Since this is denied to the eyes of the flesh, let
love be made perpetual by spiritual presence; love which can come
to an end has never been true love.
“Let us therefore aim at that which is never to have an end, where
is blessed eternity and eternal blessedness. That ye may deserve to
attain to this, let no labour affright you, no blandishments of this life
keep you back. Let there always burn in your hearts the love of Him
that appeared as their companion on the way to the two apostles,
who, when He was removed from their carnal eyes, said ‘Did not our
hearts burn within us, while He talked with us by the way, and while
He opened to us the Scriptures?’ In the writings of the holy fathers
let us seek Him whom they, not yet learned in the Scriptures,
understood. Now all is open; now He has opened the meaning of
Whom it was said ‘Then opened He their understanding, that they
might understand the Scriptures.’ Now the gospel truth shines forth
in all the world; now the enigmas of the prophets are clearer than the
sun in the churches of Christ. This light of truth follow ye with your
whole soul and understand Christ; in it love Christ, follow Christ; that
cleaving to His most sacred footsteps ye may merit to have in His
most holy presence life eternal.
“Be mindful of the apostolic mandate,[286] ‘My brethren, be ye
stedfast, unmovable; always in the work of the Lord; forasmuch as
ye know that your labour is not in vain in the Lord.’ Be stedfast in
your own place and in the devotion of your purpose. Leave not your
most holy father. Stand about his sepulchre, that he may offer your
prayers to Almighty God. Desire not the vanities of the world, but
love celestial blessings. ‘And,’ as the teacher of the Gentiles says,
[287] ‘be not conformed to this world, but be ye transformed by the
renewing of your mind.’ It is a base thing for a monk to lose the
spiritual warfare and to immerse himself in the affairs of the world.
“Let there be no murmurings among you, no hatreds, no envyings,
no evil speakings.[288] Judge not one another. Let everything be
done in humility and concord, in obedience to those set over you, not
to the eye only but from the heart, as in the presence of God. Let
your obedience, your love, your humility be known to all, that very
many may be taught by your good examples and may advance in
the salvation of their souls.
“If the venerable father Bouulf,[289] my most loved friend, is unable
by reason of his weakness to observe the full hardness of the life by
rule, judge ye not him, but obey him from your heart and love him as
a father, for he will have to give account of your souls. He labours for
you in wanderings and journeyings, that you may live quiet and keep
the life by rule and have what is necessary for your bodies. Do you
act as very dear sons. Fear God, love God, and have care of your
most holy father in your prayers, that he may live in long prosperity
with you, and that he with you and you with him may merit to have
everlasting life.
“Warn, instruct, teach your young men in all holy discipline and
Catholic doctrine; that they may be held worthy to stand in the place
of you and to send up prayers for you wherever you may remain.
Warn them about chastity of body, about confession of their sins,
about study and manual labour without murmur, and about all things
which seem necessary at their age. And let them become subject to
their elders and masters in good humility, in most pious religion. And
do you who are older afford to them good examples, so that they
may learn not from your words only but by the religion of your life.
Let them not be given to luxury, not slaves to drink, not despisers,
not following empty games; but let them learn to be good servants in
the house of God, that by the intercession of holy Boniface their
father they may deserve to receive from the God Christ blessing and
favour.
“And as to myself, I pray you have me in perpetual recollection
with yourselves in your holy prayers. For the time is at hand which
no man can escape. Let each one prepare himself, that he may
appear in the presence of his God not naked but clothed with good
practices.
“I have sent a pall for the body of the holy Boniface our father, on
whose holy intercession for my sins I place great reliance; that I, a
sinner, may even merit pardon in that day, when your holiness shall
receive the crown of eternal blessedness.
“To you, O most holy presbyters, I have sent a little collection of
words for the Mass, for use on various days on which any one
desires to offer prayers to God, whether in honour of the Holy
Trinity[290], or in love of wisdom, or in tears of penitence, or in perfect
love, or asking for angelic support, or in address to any one of all the
saints; or if any one wish to offer prayers for his own sins, or for any
living friend, or for many friends, or for brothers departing this life; or,
especially, when one wishes to invoke the intercessions of blessed
Mary, mother of God, ever virgin; or when any desires to chant and
invoke by his prayers the most pious presence of the most holy
Boniface your father. All these things we have been at the pains to
send to you by the intuition of love, praying your humility to receive
benignantly that which with the fullest love we send you. Let each
make of it such use as each pleases; and blame me not in this office
of love. Let each be fully persuaded in his own mind[291] and do
always such things as are pleasing to God and all saints, that with
them they may be found worthy to enjoy the perpetual vision of our
Lord Jesus Christ.
“May the Lord God hearken to your holy blessedness mindful of
me in all holy supplication, and deign to grant unto you present
felicity and future beatitude, my most loved brothers.
“I beg that you make known to me by letter from your blessedness,
if this letter reaches you, and what it pleases your prudence to do.
What it is mine to do I have done, fulfilling the office of affection in
the love and honour of our Lord Jesus Christ.”
 APPENDIX B
(Page 91)

We have the report which the legates George and Theophylact

sent to Pope Hadrian on their mission. No reference is made in it to
the matter of the Archbishopric of Lichfield. Iaenbricht is still the sole
southern archbishop, and Higbert of Lichfield is only bishop.
“Your holy prayers favouring us, we set sail with Ep. 10. a.d. 786.
joyous countenance obeying your commands. But
the tempter hindered us with a contrary wind. He who stills the
waves hearkened unto your deprecatory entreaty, calmed the blue
strait, led us across to a safe haven, and brought us to the shore of
the English unharmed, but afflicted with many dangers.
“We were received first by Iaenberht, Archbishop of the holy
church of Dorovernia,[292] whose other name is Cantia, where the
holy Augustine rests in the body; dwelling there we gave him the
necessary information.
“Going on thence, we arrived at the dwelling of Offa, King of the
Mercians. With great joy, for reverence of the blessed Peter and
honour of your apostolate, he received both us and the messages
sent from the highest see. Then Offa the King of the Mercians, and
Cynewulf the King of the West Saxons, came together in a council to
which we delivered your holy writings; and they forthwith promised
that they would correct the vices named.[293] Then, after counsel
held with the said kings, pontiffs, and elders of the land, considering
that that corner of the world stretches far and wide, we gave
permission to Theophylact, the venerable bishop, to go to the King of
the Mercians[294] and the parts of Britain.
“I for my part, taking with me the companion whom your most
excellent King Karl sent with us out of reverence to your apostolate,